CN104837839A - Heteroaromatic compounds as dopamine D1 ligands - Google Patents

Heteroaromatic compounds as dopamine D1 ligands Download PDF

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CN104837839A
CN104837839A CN201380063892.3A CN201380063892A CN104837839A CN 104837839 A CN104837839 A CN 104837839A CN 201380063892 A CN201380063892 A CN 201380063892A CN 104837839 A CN104837839 A CN 104837839A
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alkyl
yuan
compound
cycloalkyl
formula
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J·E·达沃伦
A·B·杜奈
I·V·叶夫列莫夫
D·L·F·格雷
S·R·门特
S·V·奥尼尔
B·N·罗杰斯
C·苏布拉曼亚姆
L·张
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Pfizer Inc
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Abstract

The present invention provides heteroaromatic compounds as dopamine D1 ligands, in particular, in part, compounds of Formula I and pharmaceutically acceptable salts thereof and N-oxides of the foregoing. According to the invention, processes for the preparation are also disclosed, together with intermediates used in the preparation of, and compositions containing such compounds, salts or N-oxides, and their uses for treating D1-mediated (or D1-associated) disorders including, e.g., schizophrenia (e.g., its cognitive and negative symptoms), cognitive impairment (e.g., cognitive impairment associated with schizophrenia, AD, PD, or pharmacotherapy therapy), ADHD, impulsivity, compulsive gambling, overeating, autism spectrum disorder, MCI, age-related cognitive decline, dementia, RLS, Parkinson's disease, Huntington's chorea, anxiety, depression, MDD, TRD, and bipolar disorder.

Description

As the heteroaromatics of dopamine D 1 part
Invention field
The present invention relates generally to heteroaromatics, and it is dopamine D 1 part, such as dopamine D 1 agonist or partial agonist.
Background of invention
Dopamine HCL is worked to neurone by two kinds of dopamine receptor families (D1 sample acceptor (D1R) and D2 sample acceptor (D2R)).D1 sample receptor family is made up of D1 and the D5 acceptor of expressing in many regions of brain.In such as striatum and nucleus accumbens septi (nucleus accumbens), find D1mRNA.See such as Missale C, Nash SR, Robinson SW, Jaber M, Caron MG " Dopaminereceptors:from structure to function ", Physiological Reviews 78:189-225 (1998).Pharmaceutical research has reported that D1 and D5 acceptor (D1/D5) (i.e. D1 sample acceptor) is relevant with the stimulation of adenylate cyclase, and D2, D3 and D4 acceptor (i.e. D2 sample acceptor) is relevant with the suppression that cAMP produces.
D1 dopamine receptor involves a large amount of neuropharmacology and neurobiological function.Such as, D1 acceptor relates to dissimilar memory function and synaptic plasticity.See people such as such as Goldman-Rakic PS, " Targeting the dopamine D1receptor in schizophrenia:insights for cognitivedysfunction ", Psychopharmacology 174 (1): 3-16 (2004).In addition, D1 acceptor has involved multiple spirit, neural, neurodevelopment, neurodegeneration, mood, motivation, metabolism, cardiovascular, kidney, eye, internal secretion and/or other illness described herein, comprise schizophrenia (the cognitive symptom in such as schizophrenia and negative symptom), the cognitive impairment relevant to D2 antagonist therapy, ADHD, impulsion, autism spectrum disorder (autism spectrum disorder), mild cognitive impairment (MCI), the cognition decline that age is relevant, Alzheimer, Parkinson's disease (PD), Huntington chorea, dysthymia disorders, anxiety, refractory depression (TRD), bipolar disorder, chronic apathy, anhedonia, confirmed fatigue, posttraumatic stress disorder, seasonal affective disorder, social anxiety disorder, post-natal depression, serotonin syndrome, substance abuse and pharmacological dependence, tourette's syndrome (Tourette'ssyndrome), tardive dyskinesia, drowsiness, sexual dysfunction, migraine, systemic lupus erythematous (SLE), hyperglycemia, hyperlipemia, obesity, diabetes, septicemia, post-ischemic renal tubular necrosis, renal failure, refractory edema (resistant edema), narcolepsy, hypertension, congestive heart failure, Post operation eye tension force is too low, somnopathy, other illness in pain and Mammals.See such as Goulet M, Madras BK " D (1) dopamine receptor agonists are moreeffective in alleviating advanced than mild parkinsonism in1-methyl-4-phenyl-1; 2; 3; 6-tetrahydropyridine-treated monkeys ", Journal ofPharmacology and Experimental Therapy 292 (2): 714-24 (2000); The people such as Surmeier DJ, " The role of dopamine in modulating the structure and function of striatalcircuits ", Prog.Brain Res.183:149-67 (2010).
In order to research and develop novel and more effective medicine treat the disease relevant to D1 deregulated activation or the patient's condition (all as described in this article those), need adjustment (such as excitement or the partial agonist) novelty of D1 or the medicament of improvement.
Summary of the invention
The present invention's part provides the compound of formula I:
Or its pharmacy acceptable salt, wherein:
X 1for N or CT 4;
Q 1for 5 yuan to the 6 yuan heteroaryls containing N or 5 yuan to the 6 yuan Heterocyclylalkyls containing N, it is separately optionally by a R 9replace, and further optionally by 1,2,3 or 4 R 10replace;
T 1, T 2, T 3and T 4be selected from independently of one another: H, halogen ,-CN, C 1-4alkyl, C 1-4haloalkyl, cyclopropyl, fluorine cyclopropyl, C 1-4alkoxyl group, C 1-4halogenated alkoxy and-C (=O)-O-(C 1-4alkyl);
R 1and R 2be selected from independently of one another: H, halogen ,-CN, C 1-6alkyl, C 1-6haloalkyl, C 1-6alkoxyl group, C 1-6halogenated alkoxy, C 3-6cycloalkyl ,-C (=O) OH and-C (=O)-O-(C 1-4alkyl), wherein said C 1-6alkyl and C 3-6cycloalkyl is optionally selected from following substituting group independently of one another by 1,2,3,4 or 5 separately and replaces: halo ,-OH ,-CN, C 1-4alkyl, C 1-4haloalkyl, C 1-4alkoxyl group and C 1-4halogenated alkoxy;
R 3and R 4be selected from independently of one another: H, halogen ,-OH ,-NO 2,-CN ,-SF 5, C 1-6alkyl, C 1-6haloalkyl, C 1-6halogenated alkoxy, C 2-6thiazolinyl, C 2-6alkynyl, C 3-7cycloalkyl, 4 yuan to 10 yuan Heterocyclylalkyls ,-N (R 5) (R 6) ,-N (R 7) (C (=O) R 8) ,-C (=O)-N (R 5) (R 6) ,-C (=O) R 8,-C (=O)-OR 8,-N (R 7) (S (=O) 2r 8) ,-S (=O) 2-N (R 5) (R 6) ,-SR 8and-OR 8, wherein said C 1-6alkyl, C 3-7cycloalkyl and Heterocyclylalkyl are optionally selected from following substituting group independently of one another by 1,2 or 3 separately and replace: halogen ,-CN ,-OH, C 1-4alkyl, C 1-4alkoxyl group, C 1-4haloalkyl, C 1-4halogenated alkoxy, C 3-6cycloalkyl ,-N (R 5) (R 6) ,-N (R 7) (C (=O) R 8) ,-C (=O)-OR 8,-C (=O) H ,-C (=O) R 8,-C (=O) N (R 5) (R 6) ,-N (R 7) (S (=O) 2r 8) ,-S (=O) 2-N (R 5) (R 6) ,-SR 8and-OR 8;
R 5for H, C 1-4alkyl, C 1-4haloalkyl or C 3-7cycloalkyl;
R 6for H or be selected from: C 1-4alkyl, C 1-4haloalkyl, C 3-7cycloalkyl, 4 yuan to 10 yuan Heterocyclylalkyls, C 6-10aryl, 5 yuan to 10 yuan heteroaryls, (C 3-7cycloalkyl)-C 1-4alkyl-, (4 yuan to 10 yuan Heterocyclylalkyls)-C 1-4alkyl-, (C 6-10aryl)-C 1-4alkyl-and (5 yuan to 10 yuan heteroaryls)-C 1-4alkyl-, wherein above-mentioned the respective option is optionally selected from following substituting group independently of one another by 1,2,3 or 4 and replaces :-OH ,-CN, C 1-4alkyl, C 3-7cycloalkyl, C 1-4hydroxyalkyl ,-S-C 1-4alkyl ,-C (=O) H ,-C (=O)-C 1-4alkyl ,-C (=O)-O-C 1-4alkyl ,-C (=O)-NH 2,-C (=O)-N (C 1-4alkyl) 2, C 1-4haloalkyl, C 1-4alkoxyl group and C 1-4halogenated alkoxy;
Or R 5and R 6form 4 yuan to 10 yuan Heterocyclylalkyls or 5 yuan to 10 yuan heteroaryls together with the atom N that they connect, it is optionally selected from following substituting group independently of one another by 1,2,3,4 or 5 separately and replaces: halogen ,-OH, oxo ,-C (=O) H ,-C (=O) OH ,-C (=O)-C 1-4alkyl ,-C (=O)-NH 2,-C (=O)-N (C 1-4alkyl) 2,-CN, C 1-4alkyl, C 1-4alkoxyl group, C 1-4hydroxyalkyl, C 1-4haloalkyl and C 1-4halogenated alkoxy;
R 7be selected from: H, C 1-4alkyl and C 3-7cycloalkyl;
R 8be selected from: C 1-6alkyl, C 3-7cycloalkyl, 4 yuan to 14 yuan Heterocyclylalkyls, C 6-10aryl, 5 yuan to 10 yuan heteroaryls, (C 3-7cycloalkyl)-C 1-4alkyl-, (4 yuan to 10 yuan Heterocyclylalkyls)-C 1-4alkyl-, (C 6-10aryl)-C 1-4alkyl-and (5 yuan to 10 yuan heteroaryls)-C 1-4alkyl-, wherein above-mentioned the respective option is optionally selected from following substituting group independently of one another by 1,2 or 3 and replaces: halogen ,-CF 3,-CN ,-OH, oxo ,-S-C 1-4alkyl, C 1-4alkyl, C 1-4haloalkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 3-7cycloalkyl, C 1-4alkoxyl group and C 1-4halogenated alkoxy;
R 9for C 1-4alkyl, C 1-4haloalkyl ,-CN ,-SF 5,-N (R 5) (R 6), C 1-6alkoxyl group, C 1-6halogenated alkoxy, C 3-7cycloalkyloxy or C 3-7cycloalkyl, wherein said C 1-4alkyl and C 3-7cycloalkyl is optionally selected from following substituting group independently of one another by 1,2,3,4 or 5 separately and replaces: halogen ,-N (R 5) (R 6), C 1-4alkyl, C 1-4haloalkyl, C 3-7cycloalkyl, C 1-4alkoxyl group and C 1-4halogenated alkoxy;
Each R 10independently selected from: halogen ,-OH ,-CN ,-SF 5,-NO 2, oxo, thiocarbonyl group ("=S "), C 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 1-6alkoxyl group, C 1-6halogenated alkoxy, C 3-7cycloalkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 6-10aryl, 4 yuan to 10 yuan Heterocyclylalkyls, 5 yuan to 10 yuan heteroaryls, (C 3-7cycloalkyl)-C 1-4alkyl-, (4 yuan to 10 yuan Heterocyclylalkyls)-C 1-4alkyl-, (C 6-10aryl)-C 1-4alkyl-, (5 yuan to 10 yuan heteroaryls)-C 1-4alkyl-,-N (R 5) (R 6) ,-N (R 7) (C (=O) R 8) ,-S (=O) 2n (R 5) (R 6) ,-C (=O)-N (R 5) (R 6) ,-C (=O)-R 8,-C (=O)-OR 8,-SR 8and-OR 8, wherein said C 1-6alkyl, C 3-7cycloalkyl, C 6-10aryl, 4 yuan to 10 yuan Heterocyclylalkyls, 5 yuan to 10 yuan heteroaryls, (C 3-7cycloalkyl)-C 1-4alkyl-, (4 yuan to 10 yuan Heterocyclylalkyls)-C 1-4alkyl-, (C 6-10aryl)-C 1-4alkyl-and (5 yuan to 10 yuan heteroaryls)-C 1-4alkyl-be optionally selected from following substituting group independently of one another by 1,2,3 or 4 separately to replace: halogen, OH ,-CN ,-NO 2, C 1-4alkyl, C 1-4hydroxyalkyl, C 1-4alkoxyl group ,-N (R 5) (R 6) ,-S-(C 1-4alkyl) ,-S (=O) 2-(C 1-4alkyl), C 6-10aryloxy, [optionally by 1 or 2 C 1-4(the C that alkyl replaces 6-10aryl)-C 1-4alkyl oxy-], oxo ,-C (=O) H ,-C (=O)-C 1-4alkyl ,-C (=O) O-C 1-4alkyl ,-C (=O) NH 2,-NHC (=O) H ,-NHC (=O)-(C 1-4alkyl), C 3-7cycloalkyl, 5 yuan or 6 yuan of heteroaryls, C 1-4haloalkyl and C 1-4halogenated alkoxy;
Or R 9and contiguous R 10the Q be connected with them 1on two annular atomses form fused benzene rings together or condense 5 yuan or 6 yuan of heteroaryls, its R optionally selected independently by 1,2,3,4 or 5 separately 10areplace; And
Each R 10aindependently selected from: halogen ,-OH ,-N (R 5) (R 6) ,-C (=O) OH ,-C (=O)-C 1-4alkyl ,-C (=O)-NH 2,-C (=O)-N (C 1-4alkyl) 2,-CN ,-SF 5, C 1-4alkyl, C 1-4alkoxyl group, C 1-4hydroxyalkyl, C 1-4haloalkyl and C 1-4halogenated alkoxy;
Condition is the compound of formula I is not 4-(4-imidazoles-1-base-phenoxy group)-3-methyl isophthalic acid H-pyrazolo [4,3-c] pyridine.
The present invention also provides composition (such as pharmaceutical composition), the compound (comprising the pharmacy acceptable salt of its N-oxide compound or described compound or described N-oxide compound) of its contained I.
The compound of formula I (comprise its N-oxide compound, and the pharmacy acceptable salt of described compound or described N-oxide compound) be D1 conditioning agent (such as D1 agonist or partial agonist).Correspondingly, the present invention further provides the illness (such as cognitive impairment, the cognitive impairment that such as relevant to schizophrenia cognitive impairment or Ahl tribulus sea silent sickness are correlated with that are used for the treatment of D1 mediation (or D1 is correlated with); Schizophrenia; Alzheimer's disease or Parkinson's disease) method, it comprises and effectively regulates the compound of the formula I of the amount of (such as exciting or partial agonist) D1 (comprise its pharmacy acceptable salt, or the N-oxide compound of described compound or salt) to its Mammals (such as people) administration of needs.
As used herein, the term " vicinity " describing two substituent relative positions on ring structure refers to two substituting groups be connected to respectively on two ring member nitrogen atoms of identical ring, and wherein said two ring member nitrogen atoms are directly connected by chemical bond.Such as, in each following structure:
Two R 70each in group is R 60adjacent group.
As used herein, wherein n is term " n unit " the usual number describing ring member nitrogen atoms in group of integer, and wherein the number of ring member nitrogen atoms is n.Such as, pyridine is the example of 6 yuan of heteroaryl rings, and thiophene is the example of 5 yuan of heteroaryls.
Multiple in this manual position, the substituting group of compound of the present invention is open with the form of group or scope.Particularly, intention makes each and each the independent sub-portfolio (subcombination) of the member that the present invention includes such group and scope.Such as, term " C 1-6alkyl " be specifically intended to comprise C 1alkyl (methyl), C 2alkyl (ethyl), C 3alkyl, C 4alkyl, C 5alkyl and C 6alkyl.In addition such as, term " 5 yuan to 10 yuan of heteroaryls " concrete intention comprises any 5 yuan, 6 yuan, 7 yuan, 8 yuan, 9 yuan or 10 yuan of heteroaryls.
As used herein, term " alkyl " is defined as and comprises saturated aliphatic hydrocarbon, and described saturated aliphatic hydrocarbon comprises straight chain and attachment.In some embodiments, alkyl has 1 to 6, such as 1 to 4 carbon atom.Such as, as used herein, term " C 1-6alkyl " and other group (such as C mentioned herein 1-6alkoxyl group) moieties refer to the group (such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl or n-hexyl) of the linear of 1 to 6 carbon atom or branching, it is optionally replaced by the substituting group that 1 or multiple (such as 1 to 5) are applicable to.Term " C 1-4alkyl " refer to the aliphatics hydrocarbon chain (i.e. methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl) of the linear of 1 to 4 carbon atom or branching.Term " C 1-3alkyl " refer to the aliphatics hydrocarbon chain of the linear of 1 to 3 carbon atom or branching.
As used herein, term " thiazolinyl " refers to the aliphatic hydrocarbon with at least one carbon-carbon double bond, and it comprises the straight chain and attachment with at least one carbon-carbon double bond.In some embodiments, described thiazolinyl has 2 to 6 carbon atoms.In some embodiments, described thiazolinyl has 2 to 4 carbon atoms.Such as, as used herein, term " C 2-6thiazolinyl " mean the unsaturated group of the straight or branched of 2 to 6 carbon atoms; and it includes, but is not limited to vinyl, 1-propenyl, 2-propenyl (allyl group), pseudoallyl, 2-methyl-1-propylene base, 1-butylene base, crotyl etc., and it is optionally replaced by 1 to 5 applicable substituting group.When the compound of formula I contains a thiazolinyl, this thiazolinyl can pure E form, pure Z-shaped formula or its any mixture form exist.
As used herein, term " alkynyl " refers to the aliphatic hydrocarbon with at least one carbon carbon triple bond, and it comprises the straight chain and attachment with at least one carbon carbon triple bond.In some embodiments, described alkynyl has 2 to 6 carbon atoms.Such as, as used herein, term " C used herein 2-6alkynyl " mean to have the hydrocarbon chain alkynyl of the linear or branching as hereinbefore defined of 2 to 6 carbon atoms and a triple bond, it is optionally replaced by the substituting group that 1 or multiple (such as 1 to 5) are applicable to.
As used herein, term " cycloalkyl " refers to saturated or undersaturated non-aromatic monocyclic or many rings (such as dicyclo) hydrocarbon ring (such as monocycle, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl, or dicyclo, comprise volution, condense or bridging system (such as dicyclo [1.1.1] amyl group, dicyclo [2.2.1] heptyl, dicyclo [3.2.1] octyl group or dicyclo [5.2.0] nonyl, decahydronaphthalene naphthyl etc.), it is optionally replaced by the substituting group that 1 or multiple (such as 1 to 5) are applicable to.Described cycloalkyl has 3 to 15 carbon atoms.In some embodiments, described cycloalkyl optionally comprises one, two or more non-accumulated (non-cumulative) non-aromatic double bond or triple bond and/or one to three oxo group.In some embodiments, bicyclic alkyl has 6 to 15 carbon atoms.Such as, term " C 3-7cycloalkyl " refer to the saturated of 3 to 7 ring carbons or undersaturated non-aromatic monocyclic or many rings (such as dicyclo) hydrocarbon ring (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or dicyclo [1.1.1] amyl group).In addition such as, term " C 3-6cycloalkyl " refer to the saturated of 3 to 6 ring carbons or undersaturated non-aromatic monocyclic or many rings (such as dicyclo) hydrocarbon ring.Again in addition such as, term " C 3-4cycloalkyl " cyclopropyl or cyclobutyl.The group of the aromatic ring (comprising aryl and heteroaryl) that there is one or more and be fused to cycloalkyl ring is also comprised in the definition of cycloalkyl, the benzo of such as pentamethylene, cyclopentenes, hexanaphthene etc. or thienyl derivative (such as 2,3-dihydro-1H-indenes-1-bases or 1H-indenes-2 (3H)-one-1-base).Cycloalkyl is optionally replaced by the substituting group that 1 or multiple (such as 1 to 5) are applicable to.
As used herein, term " aryl " refers to full carbon monocycle or the fused rings polycyclic aromatic group with conjugated pi electron system.Aryl has 6 or 10 carbon atoms in one or more ring.Aryl is everlasting in ring and has 6 carbon atoms most.Such as, as used herein, term " C 6-10aryl " mean the aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl.Aryl is optionally replaced by the substituting group that 1 or multiple (such as 1 to 5) are applicable to.
As used herein, term " heteroaryl " refers to monocycle or the fused rings polycyclic aromatic heterocyclic group at least one ring with one or more heteroatom ring members being selected from O, S and N independently of one another (ring member nitrogen atoms).Heteroaryl has 5 to 14 ring member nitrogen atoms, and it comprises the heteroatoms that 1 to 13 carbon atom and 1 to 8 are selected from O, S and N.In some embodiments, described heteroaryl has 5 to 10 ring member nitrogen atoms (comprising one to four heteroatoms).Described heteroaryl also can contain one to three oxo or thiocarbonyl group.In some embodiments, described heteroaryl has 5 to 8 ring member nitrogen atoms (comprising one, two or three heteroatoms).The example of bicyclic heteroaryl comprises those with 5 ring member nitrogen atoms (comprising one to three heteroatoms), or has 6 ring member nitrogen atoms (comprising one, two or three nitrogen heteroatom) those.The example of fused bicyclic heteroaryl group comprises two 5 yuan and/or 6 yuan of monocycles (comprising one to four heteroatoms) condensed.
The example of heteroaryl comprises pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrryl, oxazolyl (such as 1,3-oxazolyl, 1,2-oxazolyl), thiazolyl (such as 1,2-thiazolyl, 1,3-thiazoles base), pyrazolyl, tetrazyl, triazolyl (such as 1,2,3-triazoles base, 1,2,4-triazolyl), oxadiazolyl (such as 1,2,3-oxadiazolyl), thiadiazolyl group (such as 1,3,4-thiadiazolyl group), quinolyl, isoquinolyl, benzothienyl, benzofuryl, indyl, 1H-imidazo [4,5-c] pyridyl, imidazo [1,2-a] pyridyl, 1H-pyrrolo-[3,2-c] pyridyl, imidazo [1,2-a] pyrazinyl, imidazo [2,1-c] [1,2,4] triazinyl, imidazo [1,5-a] pyrazinyl, imidazo [1,2-a] pyrimidyl, 1H-indazolyl, 9H-purine radicals, imidazo [1,2-a] pyrimidyl, [1,2,4] triazolo [1,5-a] pyrimidyl, [1,2,4] triazolo [4,3-b] pyridazinyl, isoxazole is [5,4-c] pyridazinyl also, isoxazole is [3,4-c] pyridazinyl also, pyridone, pyrimidone (pyrimidone), pyrazinones, pyrimidone (pyrimidinone), 1H-imidazoles-2 (3H)-one, 1H-pyrroles-2,5-diketone, 3-oxo-2H-pyridazinyl, 1H-2-oxo-pyrimidinyl, 1H-2-oxo-pyridinyl, 2,4 (1H, 3H)-dioxo-pyrimidyl, 1H-2-oxo-pyrazinyl etc.Heteroaryl is optionally replaced by the substituting group that 1 or multiple (such as 1 to 5) are applicable to.
As used herein, term " containing N's " means described heteroaryl or Heterocyclylalkyl and comprises at least one and become ring nitrogen (N) atom and one or more optional (such as 1,2,3 or 4) to be selected from the one-tenth ring hetero atom of O, S and N independently of one another when being combined with heteroaryl or Heterocyclylalkyl.Term " 5 yuan to the 10 yuan heteroaryls containing N " refers to that comprising at least one becomes ring nitrogen (N) atom and one or more optional (such as 1,2,3 or 4) to be selected from 5 yuan to 10 yuan heteroaryls (comprising monocycle or bicyclic system) of the one-tenth ring hetero atom of O, S and N independently of one another.Term " 5 yuan or 6 yuan of heteroaryls containing N " refers to that comprising at least one becomes ring nitrogen (N) atom and one or more optional (such as 1,2,3 or 4) to be selected from 5 yuan or 6 yuan of heteroaryls of the one-tenth ring hetero atom of O, S and N independently of one another.5 yuan of examples to 10 yuan of heteroaryls containing N comprise pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, imidazolyl, pyrryl, oxazolyl (such as 1,3-oxazolyl, 1,2-oxazolyl), thiazolyl (such as 1,2-thiazolyl, 1,3-thiazoles base), pyrazolyl, tetrazyl, triazolyl (such as 1,2,3-triazoles base, 1,2,4-triazolyl), oxadiazolyl (such as 1,2,3-oxadiazolyl), thiadiazolyl group (such as 1,3,4-thiadiazolyl group), quinolyl, isoquinolyl, 1H-imidazo [4,5-c] pyridyl, imidazo [1,2-a] pyridyl, 1H-pyrrolo-[3,2-c] pyridyl, imidazo [1,2-a] pyrazinyl, imidazo [2,1-c] [1,2,4] triazinyl, imidazo [1,5-a] pyrazinyl, imidazo [1,2-a] pyrimidyl, 1H-indazolyl, 9H-purine radicals, imidazo [1,2-a] pyrimidyl, [1,2,4] triazolo [1,5-a] pyrimidyl, [1,2,4] triazolo [4,3-b] pyridazinyl, isoxazole is [5,4-c] pyridazinyl also, isoxazole is [3,4-c] pyridazinyl also, pyridone, pyrimidone (pyrimidone), pyrazinones, pyrimidone (pyrimidinone), 1H-imidazoles-2 (3H)-one, 1H-pyrroles-2,5-diketone, 3-oxo-2H-pyridazinyl, 1H-2-oxo-pyrimidinyl (such as 1H-2-oxo-pyrimidine-6-base), 1H-2-oxo-pyridinyl, 2,4 (1H, 3H)-dioxo-pyrimidyl, 1H-2-oxo-pyrazinyl etc.Example containing 5 yuan or the 6 yuan heteroaryls of N comprises pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, imidazolyl, pyrryl, oxazolyl (such as 1, 3-oxazolyl, 1, 2-oxazolyl), thiazolyl (such as 1, 2-thiazolyl, 1, 3-thiazolyl), pyrazolyl, tetrazyl, triazolyl (such as 1, 2, 3-triazolyl, 1, 2, 4-triazolyl), oxadiazolyl (such as 1, 2, 3-oxadiazolyl), thiadiazolyl group (such as 1, 3, 4-thiadiazolyl group), 3-oxo-2H-pyridazinyl, 1H-2-oxo-pyrimidinyl (such as 1H-2-oxo-pyrimidine-6-base), 1H-2-oxo-pyridinyl, 2, 4 (1H, 3H)-dioxo-pyrimidyl and 1H-2-oxo-pyrazinyl.Containing 5 yuan to the 10 yuan heteroaryls of N or optionally replaced by the substituting group that 1 or multiple (such as 1 to 5) are applicable to containing 5 yuan of N or 6 yuan of heteroaryls.
As used herein, term " Heterocyclylalkyl " refers to comprise 1 to 14 ring carbons and 1 to 10 and is selected from the monocycle of the one-tenth ring hetero atom of O, S and N or many rings independently of one another and [comprises 2 of condensing together an or more ring, comprise volution, condense or bridging system, such as bicyclic ring system], saturated or unsaturated non-aromatic 4 yuan to 15 yuan ring systems (such as 4 yuan to 14 yuan ring systems, 4 yuan to 10 yuan ring systems, 5 yuan to 10 yuan ring systems, 4 yuan to 7 yuan ring systems or 5 yuan to 6 yuan ring systems).Such as, term " 4 yuan to 10 yuan Heterocyclylalkyls " refers to comprise one or more monocycle being selected from the one-tenth ring hetero atom of O, S and N independently of one another or many ring fillings or unsaturated non-aromatic 4 yuan to 10 yuan ring systems.In addition such as, term " 4 yuan to 7 yuan Heterocyclylalkyls " refers to comprise one or more monocycle being selected from the one-tenth ring hetero atom of O, S and N independently of one another or many ring fillings or unsaturated non-aromatic 4 yuan to 7 yuan ring systems.Again in addition such as, term " 5 yuan to 6 yuan Heterocyclylalkyls " refers to comprise saturated or unsaturated non-aromatic 5 yuan to the 6 yuan ring systems of one or more monocycle being selected from the one-tenth ring hetero atom of O, S and N independently of one another.Described Heterocyclylalkyl is optionally replaced by the substituting group that 1 or multiple (such as 1 to 5) are applicable to.Described Heterocyclylalkyl also can comprise one to three oxo or thiocarbonyl group.
The example of such heterocycloalkyl ring comprises azetidinyl, tetrahydrofuran base, imidazolidyl, pyrrolidyl, piperidyl, piperazinyl, oxazolidinyl, thiazolidyl, pyrazolidyl, parathiazan base (thiomorpholinyl), tetrahydrochysene thiazinyl, tetrahydrochysene thiadiazine base, morpholinyl, oxetanyl, tetrahydrochysene diazine, oxazinyl, Evil thiazinyl, quinuclidinyl (quinuclidinyl), chromanyl, different chromanyl, benzoxazinyl, 2-azabicyclo [2.2.1] heptanone base, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptyl etc.Other example of heterocycloalkyl ring comprises tetrahydrofuran (THF)-2-base, tetrahydrofuran (THF)-3-base, imidazolidine-1-base, imidazolidine-2-base, imidazolidine-4-base, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidines-3-base, piperidin-4-yl, piperazine-1-base, piperazine-2-base, 1, 3-oxazolidine-3-base, 1, 4-oxazepine suberane-1-base, isothiazole alkyl, 1, 3-thiazole pyridine-3-base, 1, 2-pyrazolidine-2-base, 1, 2-tetrahydrochysene thiazine-2-base, 1, 3-thiazan-3-base, 1, 2-tetrahydrochysene diazine-2-base, 1, 3-tetrahydrochysene diazine-1-base, 1, 4-oxazine-4-base, oxazolidine ketone group, 2-oxo-pipehdinyl (such as 2-oxo piperidine-1-base) etc.Also comprise in the definition of Heterocyclylalkyl and there is the group that one or more is fused to the aromatic ring (comprising aryl and heteroaryl) on non-aromatic heterocyclic alkyl ring, the such as benzo derivative of pyridyl, pyrimidyl, thienyl, pyrazolyl, phthalimide-based, naphthalimido and non-aromatic heterocyclic alkyl ring.The example of such aromatics annelated heterocycles alkyl comprises indolinyl, iso-dihydro-indole-group, isoindoline-1-ketone-3-base, 5,7-dihydro-6H-pyrrolo-[3,4-b] pyridine-6-base, 6,7-dihydro-5H-pyrrolo-[3,4-d] pyrimidine-6-base, 4,5,6,7-tetramethylene sulfide also [2,3-c] pyridine-5-base, 5,6-dihydro-thiophene is [2,3-c] pyridine-7 (4H)-one-5-base, Isosorbide-5-Nitrae also, 5,6-Pyrrolidine is [3,4-c] pyrazoles-5-base and 3,4-dihydro-isoquinoline-1 (2H)-one-3-base also.Described Heterocyclylalkyl is optionally replaced by the substituting group that 1 or multiple (such as 1 to 5) are applicable to.The example of described Heterocyclylalkyl comprises 5 yuan or 6 yuan of monocycles and 9 yuan or 10 yuan of condensed-bicyclics.
As used herein, term " 4 yuan to the 10 yuan Heterocyclylalkyls containing N " refers to comprise at least one and becomes ring nitrogen (N) atom and optional one or more to be selected from 4 yuan to 10 yuan Heterocyclylalkyls of the one-tenth ring hetero atom of O, S and N independently of one another.Term " 5 yuan or 6 yuan of Heterocyclylalkyls containing N " refers to comprise at least one and becomes ring nitrogen (N) atom and optional one or more to be selected from 5 yuan or 6 yuan of Heterocyclylalkyls of the one-tenth ring hetero atom of O, S and N independently of one another.4 yuan of examples to 10 yuan of Heterocyclylalkyls containing N comprise azetidinyl, piperidin-1-yl, piperidin-4-yl, piperazine-1-base, 1,3-thiazan-3-base, Isosorbide-5-Nitrae, 5,6-Pyrrolidine is [3,4-c] pyrazoles-5-base and 3,4-dihydro-isoquinoline-1 (2H)-one-3-base also.Example containing 5 yuan or the 6 yuan Heterocyclylalkyls of N comprises piperidin-1-yl, piperidin-4-yl, piperazine-1-base, 1,3-thiazan-3-base and morpholino base.Containing 4 yuan to the 10 yuan Heterocyclylalkyls of N or optionally replaced by the substituting group that 1 or multiple (such as 1 to 5) are applicable to containing 5 yuan of N or 6 yuan of Heterocyclylalkyls.
As used herein, term " halo " or " halogen " group definition are for comprising fluorine, chlorine, bromine or iodine.
As used herein, term " haloalkyl " refers to the alkyl (whole haloalkyl at the most, namely each hydrogen atom of alkyl is all replaced by halogen atom) with one or more halogenic substituent.Such as, term " C 1-6haloalkyl " refer to the C with one or more halogenic substituent 1-6alkyl (whole haloalkyl at the most, namely each hydrogen atom of alkyl is all replaced by halogen atom).Term " C 1-4haloalkyl " refer to the C with one or more halogenic substituent 1-4alkyl (whole haloalkyl at the most, namely each hydrogen atom of alkyl is all replaced by halogen atom).Term " C 1-3haloalkyl " refer to the C with one or more halogenic substituent 1-3alkyl (whole haloalkyl at the most, namely each hydrogen atom of alkyl is all replaced by halogen atom).Term " C 1haloalkyl " refer to the methyl with one, two or three halogenic substituent.The example of haloalkyl comprises CF 3, C 2f 5, CHF 2, CH 2f, CH 2cF 3, CH 2cl etc.
As used herein, term " alkoxyl group " or " alkyl oxy " refer to-O-alkyl.Term " C 1-6alkoxyl group " or " C 1-6alkyl oxy " refer to-O-(C 1-6alkyl).Term " C 1-4alkoxyl group " or " C 1-4alkyl oxy " refer to-O-(C 1-4alkyl).Term " C 1-3alkoxyl group " or " C 1-3alkyl oxy " refer to-O-(C 1-3alkyl).The example of alkoxyl group comprises methoxyl group, oxyethyl group, propoxy-(such as positive propoxy and isopropoxy), tert.-butoxy etc.
As used herein, term " halogenated alkoxy " refers to-O-haloalkyl.Term " C 1-6halogenated alkoxy " refer to-O-(C 1-6haloalkyl).Term " C 1-4halogenated alkoxy " refer to-O-(C 1-4haloalkyl).Term " C 1-3halogenated alkoxy " refer to-O-(C 1-3haloalkyl).Term " C 1halogenated alkoxy " refer to the methoxyl group with one, two or three halogenic substituent.The example of halogenated alkoxy is-OCF 3or-OCHF 2.
As used herein, term " cycloalkyloxy " or " cycloalkyl oxy " refer to-O-cycloalkyl.Term " C 3-7cycloalkyloxy " or " C 3-7cycloalkyl oxy " refer to-O-(C 3-7cycloalkyl).The example of cycloalkyloxy comprises C 3-7cycloalkyloxy (such as ring propoxy-, cyclobutoxy group, cyclopentyloxy etc.
As used herein, term " C 6-10aryloxy " refer to-O-(C 6-10aryl).C 6-10the example of aryloxy is-O-phenyl [i.e. phenoxy group].
As used herein, term " fluoroalkyl " refers to the alkyl (perfluoroalkyl at the most, namely each hydrogen atom of alkyl is all replaced by fluorine) with one or more fluoro substituents.Such as, term " C 1-6fluoroalkyl " refer to the C with one or more fluoro substituents 1-6alkyl (perfluoroalkyl at the most, i.e. C 1-6each hydrogen atom of alkyl is all replaced by fluorine.Term " C 1fluoroalkyl " refer to the C with 1,2 or 3 fluoro substituents 1alkyl (i.e. methyl).The example of fluoroalkyl comprises CF 3, C 2f 5, CH 2cF 3, CHF 2, CH 2f etc.
As used herein, term " Fluoroalkyloxy " refers to-O-fluoroalkyl.Term " C 1fluoroalkyloxy " refer to the methoxyl group with one, two or three fluoro substituents.C 1the example of Fluoroalkyloxy is-OCF 3or-OCHF 2.
As used herein, term " fluorine cyclopropyl " refers to the cyclopropyl (perfluor cyclopropyl at the most, namely each hydrogen atom of cyclopropyl is all replaced by fluorine) with one or more fluoro substituents.The example of fluorine cyclopropyl comprises the fluoro-ring third of 2--1-base or 2,3-difluoro ring third-1-base.
As used herein, term " hydroxyalkyl " or " hydroxyalkyl " refer to have the substituent alkyl of one or more (such as 1,2 or 3) OH.Term " C 1-6hydroxyalkyl " or " C 1-6hydroxyalkyl " refer to that there is the substituent C of one or more (such as 1,2 or 3) OH 1-6alkyl.Term " C 1-4hydroxyalkyl " or " C 1-4hydroxyalkyl " refer to that there is the substituent C of one or more (such as 1,2 or 3) OH 1-4alkyl.The example of hydroxyalkyl comprises-CH 2oH and-CH 2cH 2oH.
As used herein, term " oxo " refers to=O.When oxo replaces on carbon atom, it forms carbonyl group [-C (=O)-] together.When an oxo replaces on sulphur atom, it forms sulfinyl group [-S (=O)-] together; When two oxos replace on sulphur atom, it forms sulphonyl groups [-S (=O) together 2-].
As used herein, term " thiocarbonyl group " refers to=S.When thiocarbonyl group replaces on carbon atom, it forms the group with-C (=S)-structure together.
As used herein, term " is optionally substituted " and means to be substituted by optional, and therefore comprises and not being substituted and the atom be substituted and group.The atom " be substituted " or group show that any hydrogen on specified atom or group can be replaced by the selection from the replacement basic group of specifying (atom at the most or each hydrogen atom on group are all replaced by the selection from the replacement basic group of specifying); condition is no more than the normal valency of specified atom or group, and replaces the stable compound of generation.Such as, if methyl (i.e. CH 3) be optionally substituted, then on carbon atom, 3 hydrogen atoms can be substituted base replacement at the most.
As used herein, unless specified otherwise, substituent tie point can be substituent any applicable position.Such as, piperidyl can be piperidin-1-yl (being connected by the atom N of piperidyl), piperidin-2-yl (being connected by the C atom of piperidyl 2-position), piperidines-3-base (being connected by the C atom of piperidyl 3-position) or piperidin-4-yl (being connected by the C atom of piperidyl 4-position).In addition such as, pyridyl (pyridinyl) (or pyridyl (pyridyl)) can be 2-pyridyl (or pyridine-2-base), 3-pyridyl (or pyridin-3-yl) or 4-pyridyl (or pyridin-4-yl).
When substituent key be shown as in through ring connect the key of two atoms time, then such substituting group can be connected to arbitrary ring member nitrogen atoms (namely key is connected to one or more hydrogen atom) in this commutable ring by key.Such as, as shown in following formula a-101, R 10can key be connected in two ring carbon atoms each, wherein each all carries hydrogen atom.In addition such as, as following group M 1shown in, R 10commutable any ring member nitrogen atoms can be connected to (namely key is connected to one or more hydrogen atom by key; Such as C or N ring member nitrogen atoms).Again in addition such as, as shown in following formula a-102 (imidazo [1,2-a] the pyrazine ring be substituted), R 10each (wherein each all carries hydrogen atom) in pyrazine ring in two ring carbon atoms can be connected to by key, and R 10aeach (wherein each all carries hydrogen atom) in imidazo ring in two ring carbon atoms can be connected to by key.
When the group be substituted or be optionally substituted is not when showing that described group key is described when being connected to the atom that substituting group passes through, then substituting group carries out key by suitable atom any in such group and connects.Such as, in the arylalkyl be substituted, arylalkyl [such as (C 6-10aryl)-C 1-4alkyl-] on substituting group can be connected to any carbon atom on the moieties of arylalkyl or aryl moiety by key.Being combined as of substituting group and/or variable is permissible, as long as such combination produces stable compound.
As mentioned above, the compound of formula I can exist as a pharmaceutically acceptable salt form, the acid salt of all compounds such as formula I and/or base addition salt.Unless otherwise indicated, otherwise as used herein phrase " pharmacy acceptable salt " comprises the acid salt or alkali salt that can exist in the compound of formula I.
The pharmacy acceptable salt of the compound of formula I comprises its acid salt and alkali salt.
The acid salt be applicable to is formed by the acid forming non-toxic salt.Example comprises acetate, adipate, aspartate, benzoate, benzene sulfonate, bicarbonate/carbonate, hydrosulfate/vitriol, borate, camsilate, Citrate trianion, cyclamate, ethanedisulphonate, esilate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/muriate, hydrobromate/bromide, hydriodate/iodide, isethionate, lactic acid salt, malate, maleic acid salt, malonate, mesylate, Methylsulfate, naphthoate (naphthylate), 2-naphthalenesulfonate, nicotinate, nitrate, Orotate, oxalate, palmitate, embonate, phosphate/phosphor acid hydrogen salt/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinafoate (xinofoate).
The alkali salt be applicable to is formed by the alkali forming non-toxic salt.Example comprises aluminium salt, arginic acid salt, dibenzylethylenediamine dipenicillin G salt, calcium salt, choline salt, diethylamine salt, diethanolamine salt, glycinate, lysine salt, magnesium salts, meglumine salt, ethanolamine salt, sylvite, sodium salt, tromethamine salt and zinc salt.
Also can form half salt (hemisalt) of acid and alkali, such as Hemisulphate and half calcium salt.
The summary of the salt be applicable to is see " Handbook of PharmaceuticalSalts:Properties, Selection, and Use " (Wiley-VCH, 2002) of Stahl and Wermuth.Method for the preparation of the pharmacy acceptable salt of the compound of formula I is well known by persons skilled in the art.
As used herein, term " formula I ", " formula I or its pharmacy acceptable salt ", " pharmacy acceptable salt of compound or the salt of [formula I] " are defined as the form of ownership of the compound comprising formula I, comprise its hydrate, solvate, isomer (comprising such as rotary stereo isomer), crystallization and non-crystalline forms, isomorph, polymorphic form, metabolite and prodrug.
As known in the art, amine compound (namely comprise one or more nitrogen-atoms those) (such as tertiary amine) can form N-oxide compound (being also called amine oxide or amine n-oxide).N-oxide compound has formula (R 100r 200r 300) N +-O -, wherein parent amine (R 100r 200r 300) N can be such as tertiary amine (such as R 100, R 200, R 300be alkyl, arylalkyl, aryl, heteroaryl etc. independently of one another), heterocycle or heteroaromatic amine [such as (R 100r 200r 300) N forms 1-Alkylpiperidine, 1-alkyl pyrrolidine, 1-phenmethyl tetramethyleneimine or pyridine jointly].Such as, imine nitrogen atom (particularly heterocycle or heteroaromatic imine nitrogen-atoms) or pyridine type nitrogen ( ) atom [nitrogen-atoms in such as pyridine, pyridazine or pyrazine] can by N-be oxidized to be formed comprise group ( ) N-oxide compound.Therefore, the Q of one or more nitrogen-atoms (such as imine nitrogen atom) as such as formula I is comprised 1the compound of the present invention of a part can form its N-oxide compound (such as single N-oxide compound, two N-oxide compound or many N-oxide compound or its mixture depend on the number of nitrogen atoms being suitable for forming stable N-oxyl compound).Such as, wherein Q 1for the compound of the formula I of pyrimidyl, pyrazinyl, pyridyl or pyridazinyl that is optionally substituted can oxidized (such as under the existence of the oxidising agent (such as metachloroperbenzoic acid) be applicable to or under the existence of the enzyme be applicable to) to form its corresponding N-oxide compound, wherein Q 1be converted into its corresponding N-oxide form.In addition such as, wherein Q 1for Q 1the compound of the formula I of-101 can be oxidized to form its corresponding N-oxide compound, wherein Q 1-101 are converted into Q 1-102.
As used herein, term " N-oxide compound " refer to amine compound described herein (such as comprising the compound of one or more imine nitrogen atom) likely and particularly all stable N-oxide forms, the such as mixture of single N-oxide compound (comprising when the different isomer when the more than one nitrogen-atoms of amine compound can form single N-oxide compound) or many N-oxide compound (such as two N-oxide compound) or its any ratio.
The compound of formula I can be optionally converted into its N-oxide compound, such as be applicable to oxidising agent exist under in be applicable to solvent in (such as in the presence of hydrogen peroxide in methyl alcohol, or under metachloroperbenzoic acid exists in methylene dichloride), or under enzyme (such as forming its N-oxide compound with metabolite form) exists.Those skilled in the art easily can recognize the reaction conditions being suitable for carrying out N-oxidizing reaction.
The compound (compound of the present invention) of formula I described herein comprises the pharmacy acceptable salt of its N-oxide compound and described compound or described N-oxide compound.The example of the N-oxide compound of the compound of formula I comprises the Q of its Chinese style I 1(pyrimidyl be such as optionally substituted, such as Q 1-101) those of its N-oxide compound can be formed.
The compound of formula I can exist from completely amorphous continuous solid-state form to complete holocrystalline scope.Term " amorphous " refers to that wherein material lacks long-range order on a molecular scale, and depends on temperature, can represent the state of the physical property of solid or liquid.Such material does not produce unique X-ray diffraction pattern usually, although and represent solid property, be more formally described as liquid.When heating, solid becomes the material with characteristics of liquids in appearance certainly, it is characterized in that the change of state, is generally secondary change (" glass transition ").Term " crystallization " refers to that wherein material has regular internal structure on a molecular scale and produces the solid phase with unique X-ray diffraction pattern at the peak determined.Such material also can represent the characteristic of liquid when abundant heating, but is phase transformation from the feature that solid becomes liquid, is generally first-order phase transition (" fusing point ").
The compound of formula I can non-solvated and solvation form existence.When solvent or water are combined closely, complex compound can have the clear and definite stoichiometry irrelevant with humidity.But when solvent or water weak binding (as in passage solvate (channel solvate) and hygroscopic compound), water/solvent can depend on humidity and drying conditions.Under these circumstances, nonstoichiometry can be mean number (norm).
The compound of formula I can the form of inclusion compound or other complex compound (such as eutectic) exist.Comprise complex compound within the scope of the invention, such as inclusion compound, drug-host inclusion complex compound (drug-hostinclusion complexe), its Chinese traditional medicine and host stoichiometrically or nonstoichiometry present.Also comprise the complex compound of the compound of the formula I of and/or inorganic component organic containing two or more, it can be stoichiometric or non-stoichiometric.Gained complex compound can be ionization, partial ionization or non-ionic.Eutectic is normally defined the crystalline complex of the neutral molecule composition combined by noncovalent interaction, but also can be the complex compound of neutral molecule and salt.Eutectic by melt crystallization, by from solvent recrystallization or by by component together physical grinding prepare; See O.Almarsson and M.J.Zaworotko, Chem.Commun.2004,17,1889-1896.The generality of polycomponent complex compound is summarized see J.K.Haleblian, J.Pharm.Sci.1975,64,1269-1288.
Compound of the present invention can also mesomorphic state (mesophase spherule or liquid crystal) form exist when standing the condition be applicable to.Mesomorphic state is the intermediate state between real crystalline state and real liquid (melt or solution).The mesomorphism occurred because of temperature variation is described as " thermotropic ", and the mesomorphism that produces because adding another component (such as water or another kind of solvent) is described as " lyotropic ".The compound with the potentiality forming lyotropic mesophase spherule is described to " amphiphilic ", and by having ion polarity head base (such as-COO -na +,-COO -k +or-SO 3 -na +) or non-ionic polar head base (such as-N -n +(CH 3) 3) molecular composition.More information see the Crystals and the PolarizingMicroscope of N.H.Hartshorne and A.Stuart, the 4th edition (Edward Arnold, 1970).
The invention still further relates to the prodrug of the compound of formula I.Therefore, itself can have seldom or do not have pharmacological activity formula I compound some derivative by body or Topical administration time such as can be converted into the compound with required active formula I by hydrolytic scission.Such derivative is called " prodrug ".The out of Memory of prodrug is used to be found in Pro-drugs as Novel Delivery Systems, 14th volume, ACS Symposium Series (T.Higuchi and W.Stella) and Bioreversible Carriers inDrug Design, Pergamon Press, in 1987 (E.B.Roche compiles, American PharmaceuticalAssociation).
Prodrug of the present invention can such as be produced by the suitable functional group coming to exist in the compound of alternate form I with some group well known by persons skilled in the art (such as described in the Design of Prodrugs (Elsevier, 1985) of H.Bundgaard " front-group ").
In addition, the compound of some formula I itself can be used as the prodrug of the compound of other formula I.
Also comprise the metabolite of the compound of formula I within the scope of the invention, the compound namely formed in body when administration medicine.The example of the metabolite of the compound of formula I comprises the N-oxide compound of the compound of formula I, the Q of its Chinese style I 1its N-oxide compound (such as wherein Q can be formed 1for the pyrimidyl be optionally substituted, such as 4,6-dimethyl pyrimidine-5-bases).
In some embodiments, the compound of formula I comprises the pharmacy acceptable salt of its N-oxide compound and described compound or described N-oxide compound.
The compound of formula I comprises all steric isomers and tautomer.The steric isomer of formula I comprises the cis of the compound of formula I and trans-isomer(ide), optical isomer (such as R and S enantiomer, diastereomer), geometrical isomer, rotational isomer, atropisomer and conformer, comprises the compound of the isomery representing more than one types; And composition thereof (such as racemic modification and diastereo-isomerism to).Also comprise acid salt or base addition salt, wherein counterion is optically active (such as D-lactate or 1B) or racemic (such as DL-tartrate or DL-arginine).
In some embodiments, the compound of formula I can have unsymmetrical carbon.The carbon-carbon bond of the compound of formula I can use in this article solid line ( ), solid wedge ( ) or dotted line wedge shape ( ) describe.The key using solid line to describe to be connected to unsymmetrical carbon means to comprise all possible steric isomer (such as concrete enantiomer, racemic mixture etc.) at this carbon atom place.The key using solid or dotted line wedge shape to describe to be connected to unsymmetrical carbon means only to be intended to comprise shown steric isomer.The compound of formula I may contain more than one unsymmetrical carbon.In those compounds, the key using solid line to describe to be connected to unsymmetrical carbon means intention and comprises all possible steric isomer.Such as, unless otherwise indicated, otherwise wish that the compound of formula I can enantiomer and diastereomeric form or exist with racemic modification and composition thereof form.Solid line is used to describe to be connected to the key of one or more unsymmetrical carbon in the compound of formula I and the key using solid wedge or dotted line wedge shape to describe to be connected to other unsymmetrical carbon in same compound means to exist the mixture of diastereomer.
In some embodiments, the compound of formula I atropisomer form can exist and/or be separated into atropisomer (such as one or more resistance turns enantiomer.One skilled in the art will realize that resistance turns isomerism and can exist in the compound with two or more aromatic rings (such as by singly linked two aromatic rings).See such as Freedman, T.B. people is waited, Absolute ConfigurationDetermination of Chiral Molecules in the Solution State Using VibrationalCircular Dichroism.Chirality 2003,15,743-758; And the people such as Bringmann, G., Atroposelective Synthesis of Axially Chiral Biaryl Compounds.Angew.Chem., Int.Ed.2005,44,5384-5427.
When any racemate crystallises, dissimilar crystal may be had.One type is racemic compound (real racemic modification), wherein produces a kind of homogeneous form crystal of the enantiomer containing two kinds of equimolar amounts.Another kind of type is racemic mixture or aggregation, wherein produces the crystal of equimolar amount or not two kinds of forms of each self-contained single enantiomer of equimolar amount.
The compound of formula I can represent tautomerism and structural isomerism.Such as, the compound of formula I can several tautomeric forms exist, and comprises enol and imines form and ketone and enamine form and geometrical isomer and composition thereof.All such tautomeric forms include in the scope of the compound of formula I.Tautomer can the form of mixtures of tautomerism set in solution exist.In solid form, usual a kind of tautomer is in the great majority.Even if a kind of tautomer may be described, the present invention includes all tautomers of the compound of formula I.Such as, when disclose in experimental section in this article of the present invention below two kinds of tautomers for the moment, those skilled in the art can easily recognize that the present invention also comprises another.
The present invention includes the compound of all pharmaceutically acceptable isotope-labeled formula I, wherein one or more atom is had same atoms ordinal number but the atom that atomic mass or total mass number are different from atomic mass or the total mass number be in the great majority at occurring in nature is replaced.
Be suitable for the isotropic substance that the isotopic example be included in compound of the present invention comprises hydrogen, such as 2h and 3h; The isotropic substance of carbon, such as 11c, 13c and 14c; The isotropic substance of chlorine, such as 36cl; The isotropic substance of fluorine, such as 18f; The isotropic substance of iodine, such as 123i and 125i; The isotropic substance of nitrogen, such as 13n and 15n; The isotropic substance of oxygen, such as 15o, 17o and 18o; The isotropic substance of phosphorus, such as 32p; And the isotropic substance of sulphur, such as 35s.
The compound of some isotope-labeled formula I (such as mix radioisotopic those) can be used for medicine and/or substrate tissue distribution research.Due to radio isotope tritium (namely 3h) and carbon-14 (namely 14c) be easy to mix and have ready-made detection means, so it is particularly useful for this object.
With such as deuterium (namely 2h) higher isotope replaces some treatment advantage that can obtain being thanked to stability generation by higher generation, and such as Half-life in vivo increases or volume requirements reduces, and therefore can be preferred in some cases.
With Positron emitting isotopes (such as 11c, 18f, 15o and 13n) replacement can be used for pet art (PET) research, to check substrate receptor occupancy.
The compound of isotope-labeled formula I (or its pharmacy acceptable salt, or the N-oxide compound of described compound or salt) usually by routine techniques well known by persons skilled in the art or by with in appended embodiment and the similar method described in preparing, use suitable isotope-labeled reagent to replace the unmarked reagent previously adopted to prepare.
An embodiment of the present invention is wherein X 1for the compound of the formula I of N.
An embodiment of the present invention is wherein X 1for CT 4the compound of formula I.
An embodiment of the present invention is wherein T 1, T 2, T 3and T 4be selected from independently of one another: H, F ,-CN, methoxyl group, C 1fluoroalkyloxy, methyl and C 1the compound of the formula I of fluoroalkyl.In another embodiment, T 1for H.In another embodiment, T 2for H.In another embodiment, T 3for H, methyl or-CN.In another embodiment, T 3for H.In another embodiment, T 4for H.
An embodiment of the present invention is wherein T 3for the compound of the formula I of H.In another embodiment, T 2for H and T 3for H.
The compound of an embodiment of the present invention to be wherein said compound the be formula I of the compound of formula Ia or Ib:
The compound of an embodiment of the present invention to be wherein said compound the be formula I of the compound of formula Ia.
The compound of an embodiment of the present invention to be wherein said compound the be formula I of the compound of formula Ib.
An embodiment of the present invention is the compound (comprising the compound of formula Ia or Ib) of formula I, wherein:
R 1and R 2be selected from independently of one another: H, halogen ,-CN, C 1-4alkyl, C 1-4haloalkyl, C 1-4alkoxyl group, C 1-4halogenated alkoxy and C 3-4cycloalkyl;
R 3and R 4be selected from independently of one another: H, halogen ,-OH ,-CN, C 1-4alkyl, C 1-4haloalkyl, C 1-4halogenated alkoxy, C 3-4cycloalkyl, 4 yuan to 7 yuan Heterocyclylalkyls ,-N (R 5) (R 6) and-OR 8;
R 5and R 6be H or be selected from: C independently of one another 1-4alkyl, C 1-4haloalkyl and C 3-7cycloalkyl;
Or R 5and R 6form 4 yuan to 7 yuan Heterocyclylalkyls or 5 yuan of heteroaryls together with the atom N that they connect, it is optionally selected from following substituting group independently of one another by 1,2 or 3 separately and replaces: halogen ,-CN, C 1-4alkyl, C 1-4alkoxyl group, C 3-6cycloalkyl, C 1-4haloalkyl and C 1-4halogenated alkoxy; And
R 8be selected from: C 1-4alkyl, C 3-6cycloalkyl, 4 yuan to 7 yuan Heterocyclylalkyls, phenyl and 5 yuan to 6 yuan heteroaryls, it is optionally selected from following substituting group independently of one another by 1,2 or 3 separately and replaces: halogen ,-CN, C 1-4alkyl, C 1-4haloalkyl, C 3-6cycloalkyl, C 1-4alkoxyl group and C 1-4halogenated alkoxy;
An embodiment of the present invention is wherein R 1and R 2be the compound (comprising the compound of formula Ia or Ib) of the formula I of H or halogen independently of one another.In another embodiment, R 1and R 2be H or F independently of one another.In another embodiment, R 1for H, and R 2for H or F.In another embodiment, R 1and R 2be H separately.
An embodiment of the present invention is wherein R 3and R 4be H, halogen ,-CN, methyl, C independently of one another 1haloalkyl, methoxyl group or C 1the compound (comprising the compound of formula Ia or Ib) of the formula I of halogenated alkoxy.In another embodiment, R 3and R 4be H, halogen ,-CN, methyl or C independently of one another 1haloalkyl.In another embodiment, R 3for H, and R 4for H, F, Cl ,-CN, methyl or C 1haloalkyl.In another embodiment, R 3for H, and R 4for H, F or methyl.In another embodiment, R 3for H, and R 4for methyl.
An embodiment of the present invention is wherein R 1for H; R 2for H or F; R 3for H; And R 4for H, F, Cl ,-CN, methyl or C 1the compound (comprising the compound of formula Ia or Ib) of the formula I of haloalkyl.In another embodiment, R 1, R 2and R 3be H separately, and R 4for H or methyl.In another embodiment, R 4for methyl.
An embodiment of the present invention is wherein R 2and R 4be the compound (comprising the compound of formula Ia or Ib) of the formula I of H separately.
An embodiment of the present invention is the compound (comprising the compound of formula Ia or Ib) of formula I, wherein:
Q 1for group (" M 1group ");
Ring Q 1afor 5 yuan to the 6 yuan heteroaryls containing N or 5 yuan to the 6 yuan Heterocyclylalkyls containing N;
represent singly-bound or double bond;
Z 1and Z 2be C or N independently of one another;
R 9for C 1-4alkyl, C 1-4haloalkyl, C 3-7cycloalkyl ,-CN ,-N (R 5) (R 6), C 1-6alkoxyl group, C 1-6halogenated alkoxy or C 3-7cycloalkyloxy, wherein said C 1-4alkyl and C 3-7cycloalkyl is optionally selected from following substituting group independently of one another by 1,2,3,4 or 5 separately and replaces: halogen ,-N (R 5) (R 6), C 1-4alkyl, C 1-4haloalkyl, C 3-7cycloalkyl, C 1-4alkoxyl group and C 1-4halogenated alkoxy;
Each R 10independently selected from: halogen ,-OH ,-CN ,-NO 2, oxo, thiocarbonyl group, C 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 1-6alkoxyl group, C 1-6halogenated alkoxy, C 3-7cycloalkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 6-10aryl, 4 yuan to 10 yuan Heterocyclylalkyls, 5 yuan to 10 yuan heteroaryls, (C 3-7cycloalkyl)-C 1-4alkyl-, (4 yuan to 10 yuan Heterocyclylalkyls)-C 1-4alkyl-, (C 6-10aryl)-C 1-4alkyl-, (5 yuan to 10 yuan heteroaryls)-C 1-4alkyl-, (5 yuan to 10 yuan heteroaryls)-C 2-4thiazolinyl-,-N (R 5) (R 6) ,-N (R 7) (C (=O) R 8) ,-S (=O) 2n (R 5) (R 6) ,-C (=O)-N (R 5) (R 6) ,-C (=O)-R 8,-C (=O)-OR 8and-OR 8, wherein said C 1-6alkyl, C 3-7cycloalkyl, C 6-10aryl, 4 yuan to 10 yuan Heterocyclylalkyls, 5 yuan to 10 yuan heteroaryls, (C 3-7cycloalkyl)-C 1-4alkyl-, (4 yuan to 10 yuan Heterocyclylalkyls)-C 1-4alkyl-, (C 6-10aryl)-C 1-4alkyl-, (5 yuan to 10 yuan heteroaryls)-C 1-4alkyl-and (5 yuan to 10 yuan heteroaryls)-C 2-4thiazolinyl-be optionally selected from following substituting group independently of one another by 1,2,3 or 4 separately to replace: halogen, OH ,-CN ,-NO 2, C 1-4alkyl, C 1-4hydroxyalkyl, C 1-4alkoxyl group ,-N (R 5) (R 6) ,-S-(C 1-4alkyl) ,-S (=O) 2-(C 1-4alkyl), C 6-10aryloxy, optionally by 1 or 2 C 1-4(the C that alkyl replaces 6-10aryl)-C 1-4alkyl oxy-, oxo ,-C (=O) H ,-C (=O)-C 1-4alkyl ,-C (=O) O-C 1-4alkyl ,-C (=O) NH 2,-NHC (=O) H ,-NHC (=O)-(C 1-4alkyl), C 3-7cycloalkyl, 5 yuan or 6 yuan of heteroaryls, C 1-4haloalkyl and C 1-4halogenated alkoxy;
Or R 9and contiguous R 10the ring Q be connected with them 1aon two annular atomses form fused benzene rings together or condense 5 yuan or 6 yuan of heteroaryls, its R optionally selected independently by 1,2,3,4 or 5 separately 10areplace;
Each R 10aindependently selected from: halogen ,-OH ,-C (=O) OH ,-C (=O)-C 1-4alkyl ,-C (=O)-NH 2,-C (=O)-N (C 1-4alkyl) 2,-CN, C 1-4alkyl, C 1-4alkoxyl group, C 1-4hydroxyalkyl, C 1-4haloalkyl and C 1-4halogenated alkoxy; And
M is 0,1,2,3 or 4.
An embodiment of the present invention is wherein Q 1for M 1group and Z 1for the compound (comprising the compound of formula Ia or Ib) of the formula I of C.
An embodiment of the present invention is wherein Q 1for M 1group and Z 1for the compound (comprising the compound of formula Ia or Ib) of the formula I of N.
An embodiment of the present invention is wherein Q 1or ring Q 1a(work as Q 1for M 1during group) be the compound (comprising the compound of formula Ia or Ib) containing the formula I of 6 yuan of heteroaryls of N be optionally substituted.In another embodiment, the ring member nitrogen atoms of 6 yuan of heteroaryls is selected from N and C independently of one another.
An embodiment of the present invention is wherein Q 1or ring Q 1a(work as Q 1for M 1during group) compound (comprising the compound of formula Ia or Ib) of the formula I of pyridyl, pyrimidyl, pyridazinyl or pyrazinyl for being optionally substituted.In another embodiment, Q 1or ring Q 1afor the pyrimidyl be optionally substituted.In another embodiment, Q 1or ring Q 1afor by 1 or 2 C 1-4alkyl (such as CH 3) pyrimidyl that replaces.
An embodiment of the present invention is wherein Q 1for M 1the compound (comprising the compound of formula Ia or Ib) of the formula I of group, described M 1group is selected from: quinolyl, isoquinolyl, 1H-imidazo [4, 5-c] pyridyl, imidazo [1, 2-a] pyridyl, 1H-pyrrolo-[3, 2-c] pyridyl, imidazo [1, 2-a] pyrazinyl, imidazo [2, 1-c] [1, 2, 4] triazinyl, imidazo [1, 5-a] pyrazinyl, imidazo [1, 2-a] pyrimidyl, 1H-indazolyl, 9H-purine radicals, [1, 2, 4] triazolo [1, 5-a] pyrimidyl, isoxazole also [5, 4-c] pyridazinyl, isoxazole also [3, 4-c] pyridazinyl and [1, 2, 4] triazolo [4, 3-b] pyridazinyl, it is separately optionally by 1, 2 or 3 R 10replace, and further optionally by 1 or 2 R 10areplace, or wherein M 1group is selected from: pyrimidyl, pyrazinyl, pyridyl, pyridazinyl, 1H-pyrazolyl, 1H-pyrryl, 4H-pyrazolyl, 1H-imidazolyl, 3-oxo-2H-pyridazinyl, 1H-2-oxo-pyrimidinyl, 1H-2-oxo-pyridinyl, 2,4 (1H, 3H)-dioxo-pyrimidyl and 1H-2-oxo-pyrazinyl, it is separately by R 9replace and further optionally by 1,2 or 3 R 10replace.
In another embodiment, M 1group is selected from: pyrimidyl, pyrazinyl, pyridyl and pyridazinyl, and it is separately by R 9replace and further optionally by 1,2 or 3 R 10replace.In another embodiment, M 1group is by R 9replace and further optionally by 1,2 or 3 R 10the pyrimidyl replaced.
An embodiment of the present invention is wherein Q 1for M 1the compound (comprising the compound of formula Ia or Ib) of the formula I of group, described M 1group is selected from: 3-oxo-2H-pyridazinyl, 2,4 (1H, 3H)-dioxo-pyrimidyl and 1H-2-oxo-pyrazinyl, it is separately by R 9replace and further optionally by 1,2 or 3 R 10replace.
An embodiment of the present invention is the compound (comprising the compound of formula Ia or Ib) of formula I, wherein:
Q 1for M 1group, described M 1group is r 10afor C 1-4alkyl, C 1-4haloalkyl or C 3-7cycloalkyl; And t is 0 or 1.
An embodiment of the present invention is wherein Q 1for M 1(it is group ) the compound (comprising the compound of formula Ia or Ib) of formula I.
An embodiment of the present invention is wherein Q 1for the compound (comprising the compound of formula Ia or Ib) of formula I.In another embodiment, Q 1for in another embodiment, Q 1it is 4,6-dimethyl pyrimidine-5-base.
An embodiment of the present invention is the compound (comprising the compound of formula Ia or Ib) of formula I, wherein:
Q 1for M 1group, described M 1group is
And
R 11for H, C 1-4alkyl, C 1-4haloalkyl or C 3-7cycloalkyl.In another embodiment, R 9and R 10(or R 11) be C independently of one another 1-4alkyl (such as CH 3).
An embodiment of the present invention is wherein Q 1for the compound (comprising the compound of formula Ia or Ib) of the formula I of 3-oxo-4,6-dimethyl-(2H) pyridazine-5-base.
An embodiment of the present invention is wherein Q 1for the compound (comprising the compound of formula Ia or Ib) of the formula I of 2-oxo-1,5-dimethyl-(1H) pyrazine-6-base.
An embodiment of the present invention is wherein Q 1it is the compound (comprising the compound of formula Ia or Ib) of the formula I of 2,4-dioxo-1,5-dimethyl-(1H, 3H) pyrimidine-6-base.
An embodiment of the present invention is wherein R 9for C 1-4the compound (comprising the compound of formula Ia or Ib) of the formula I of alkyl or-CN.In another embodiment, R 9for methyl, ethyl or-CN.In another embodiment, R 9for methyl or-CN.In another embodiment, R 9for methyl.
An embodiment of the present invention is the compound (comprising the compound of formula Ia or Ib) of formula I, wherein each R 10independently selected from: C 1-4alkyl, C 1-4haloalkyl ,-CN and-N (R 5) (R 6), wherein R 5and R 6be H or be selected from: C independently of one another 1-4alkyl, C 1-4haloalkyl and C 3-7cycloalkyl; Or R 5and R 6form 4 yuan to 7 yuan Heterocyclylalkyls or 5 yuan of heteroaryls together with the atom N that they connect, it is optionally selected from following substituting group independently of one another by 1,2 or 3 separately and replaces: halogen ,-CN, C 1-4alkyl, C 1-4alkoxyl group, C 3-6cycloalkyl, C 1-4haloalkyl and C 1-4halogenated alkoxy.In another embodiment, each R 10independently selected from: methyl, ethyl and-N (R 5) (R 6), wherein R 5and R 6form azetidinyl, pyrrolidyl or piperidyl together with the atom N that they connect, it is optionally selected from following substituting group independently of one another by 1,2 or 3 separately and replaces: halogen ,-CN, C 1-4alkyl, C 1-4alkoxyl group, C 3-6cycloalkyl, C 1-4haloalkyl and C 1-4halogenated alkoxy.In another embodiment, each R 10independently selected from: methyl, ethyl and azetidine-1-base, wherein said azetidine-1-base is optionally replaced by 1,2 or 3 halogen (such as F).
An embodiment of the present invention is wherein each R 10be C independently 1-4the compound (comprising the compound of formula Ia or Ib) of the formula I of alkyl.In another embodiment, each R 10for methyl.
In one embodiment, the present invention also provides one or more compound, its N-oxide compound described by the embodiment 1-47 in present application example part, and the pharmacy acceptable salt of described compound or described N-oxide compound.
Another embodiment of the present invention relates to and is selected from following compound:
4-[4-(4,6-dimethyl pyrimidine-5-base)-3-fluorophenoxy]-1H-pyrrolo-[3,2-c] pyridine;
(+)-4,6-dimethyl-5-[2-methyl-4-(1H-pyrazolo [4,3-c] pyridin-4-yl oxygen base) phenyl] pyridazine-3 (2H)-one;
(-)-4,6-dimethyl-5-[2-methyl-4-(1H-pyrazolo [4,3-c] pyridin-4-yl oxygen base) phenyl] pyridazine-3 (2H)-one;
4-[4-(4,6-dimethyl pyrimidine-5-base)-3-methylphenoxy]-1H-pyrrolo-[3,2-c] pyridine;
4-[4-(4,6-dimethyl pyrimidine-5-base)-3-methylphenoxy]-1H-pyrazolo [4,3-c] pyridine;
4,6-dimethyl-5-[4-(1H-pyrrolo-[3,2-c] pyridin-4-yl oxygen base) phenyl] pyridazine-3 (2H)-one;
(-)-1,5-dimethyl-6-[2-methyl-4-(1H-pyrazolo [4,3-c] pyridin-4-yl oxygen base) phenyl] pyrimidine-2,4 (1H, 3H)-diketone;
4,6-dimethyl-5-[2-methyl-4-(1H-pyrrolo-[3,2-c] pyridin-4-yl oxygen base) phenyl] pyridazine-3 (2H)-one, ENT-1;
4,6-dimethyl-5-[2-methyl-4-(1H-pyrrolo-[3,2-c] pyridin-4-yl oxygen base) phenyl] pyridazine-3 (2H)-one, ENT-2;
4-[4-(4,6-dimethyl-1-is oxidized pyrimidine-5-base)-3-methylphenoxy]-1H-pyrazolo [4,3-c] pyridine;
6-methyl-5-[2-methyl-4-(1H-pyrrolo-[3,2-c] pyridin-4-yl oxygen base) phenyl] imidazo [1,2-a] pyrazine;
4-[4-(4,6-dimethyl pyrimidine-5-base) phenoxy group]-1H-pyrrolo-[3,2-c] pyridine;
2-(4,6-dimethyl pyrimidine-5-base)-5-(1H-pyrrolo-[3,2-c] pyridin-4-yl oxygen base) cyanobenzene;
4-[the chloro-4-of 3-(4,6-dimethyl pyrimidine-5-base) phenoxy group]-1H-pyrrolo-[3,2-c] pyridine;
(-)-1,5-dimethyl-6-[2-methyl-4-(1H-pyrrolo-[3,2-c] pyridin-4-yl oxygen base) phenyl] pyrazine-2 (1H)-one;
4-[4-(4,6-dimethyl pyrimidine-5-base)-3-fluorophenoxy]-1H-pyrazolo [4,3-c] pyridine;
4-[4-(4,6-dimethyl pyrimidine-5-base)-3-methoxyphenoxy]-1H-pyrazolo [4,3-c] pyridine;
4-[the chloro-4-of 3-(4,6-dimethyl pyrimidine-5-base) phenoxy group]-1H-pyrazolo [4,3-c] pyridine;
(+)-1,5-dimethyl-6-[2-methyl-4-(1H-pyrazolo [4,3-c] pyridin-4-yl oxygen base) phenyl] pyrazine-2 (1H)-one;
4,6-dimethyl-5-[4-(1H-pyrazolo [4,3-c] pyridin-4-yl oxygen base) phenyl] pyridazine-3 (2H)-one; And
1,5-dimethyl-6-[4-(1H-pyrazolo [4,3-c] pyridin-4-yl oxygen base) phenyl] pyrimidine-2,4 (1H, 3H)-diketone,
Or its pharmacy acceptable salt.
The present invention also provides composition (such as pharmaceutical composition), the compound (comprising the pharmacy acceptable salt of its N-oxide compound or described compound or described N-oxide compound) of its contained I.Correspondingly, in one embodiment, the invention provides pharmaceutical composition, the compound (pharmacy acceptable salt of its N-oxide compound or described compound or described N-oxide compound) of it comprises (treatment significant quantity) formula I, and optionally comprise pharmaceutically acceptable carrier.In another embodiment, the invention provides pharmaceutical composition, the compound (pharmacy acceptable salt of its N-oxide compound or described compound or described N-oxide compound) of it comprises (treatment significant quantity) formula I, optionally comprises pharmaceutically acceptable carrier and the extra medicine of optional at least one or medicament (all antipsychotic drugs as described below or antischizophrinic).In one embodiment, described extra medicine or medicament are antischizophrinic as described below.
Described pharmaceutically acceptable carrier can comprise any Conventional pharmaceutical carriers or vehicle.The pharmaceutical carrier be applicable to comprises inert diluent or weighting agent, water and multiple organic solvent (such as hydrate and solvate).If desired, described pharmaceutical composition can comprise extra composition, such as seasonings, tackiness agent, vehicle etc.Therefore, for oral administration, the tablet containing multiple vehicle (such as citric acid) can be used together with multiple disintegrating agent (such as starch, Lalgine and some composition silicate) and tackiness agent (such as sucrose, gelatin and gum arabic).In addition, lubricant (such as Magnesium Stearate, Sodium Lauryl Sulphate BP/USP and talcum) often can be used for the object of compressing tablet.The solids composition of similar type can also soft filling and hard gelatine capsule agent form use of filling.Therefore, the limiting examples of material comprises lactose (lactose) or lactose (milk sugar) and high molecular weight polyethylene glycol.When aqueous suspension or elixir are used for oral administration by needs, can by wherein active compound and multiple sweeting agent or seasonings, painted thing or dyestuff and (if desired) emulsifying agent or suspending agent, and with thinner (such as water, ethanol, propylene glycol, glycerine or its combine) together with combine.
Described pharmaceutical composition such as in the form (as tablet, capsule, pill, powder, extended release preparation, solution or suspensoid) being suitable for oral administration, can be suitable for the form (as sterile solution agent, suspensoid or emulsion) of parenteral injection; Be suitable for the form (as ointment or ointment) of topical, or be suitable for the form (as suppository) of rectal administration.
Exemplary parenteral form of medication comprises the solution of active compound in aseptic aqueous solution (such as propylene glycol or D/W) or suspensoid.If desired, such formulation can suitably be cushioned.
Described pharmaceutical composition can in the unit dosage being suitable for single-dose exact dosage desired.Those of ordinary skill in the art can understand, and can be formulated as lower than therapeutic dose by described composition, for the multiple dosing of anticipation.
In one embodiment, described composition comprises the compound (or pharmacy acceptable salt of its N-oxide compound or described compound or described N-oxide compound) of the formula I for the treatment of significant quantity and pharmaceutically acceptable carrier.
The compound of formula I (comprise its N-oxide compound, and the pharmacy acceptable salt of described compound or described N-oxide compound) be D1 conditioning agent.In some embodiments, the compound of formula I is D1 agonist [namely in conjunction with D1 acceptor (having the affinity with D1 acceptor) and activate D1 acceptor].In some embodiments, when use Dopamine HCL as a reference completely D1 agonist, the compound of formula I is super-agonists (peak response that namely can produce D1 acceptor is larger than endogenous D1 agonist (Dopamine HCL), and therefore represents the compound of the effect exceeding about 100% (such as 120%)).In some embodiments, when using Dopamine HCL as reference full agonist, the compound of formula I is complete D1 agonist (namely compared with effect of Dopamine HCL, its effect is about 100%, such as 90%-100%).In some embodiments, when use Dopamine HCL as a reference completely D1 agonist, the compound of formula I is that partial agonist is [although namely compound is in conjunction with D1 acceptor and activation D1 acceptor, relative to full agonist (Dopamine HCL), it only has partial efficacy (being namely less than 100%, such as 10%-80% or 50%-70%) to D1 acceptor].D1 agonist (comprising super-agonists, full agonist and partial agonist) can the activity of exciting or partial agonist D1.In some embodiments, the compound of formula I is to the EC of D1 50for being less than about 10 μMs, 5 μMs, 2 μMs, 1 μM, 500nM, 200nM, 100nM, 50nM, 40nM, 30nM, 20nM, 10nM, 5nM, 2nM or 1nM.
The present invention is also provided for regulating the method for the activity of (such as exciting or partial agonist) D1 acceptor (external or body in), and it comprises makes D1 acceptor contact with the compound (being such as selected from the one of embodiment 1-47) of formula I or the pharmacy acceptable salt of its N-oxide compound or described compound or described N-oxide compound.
Another embodiment of the present invention comprises the method for the illness being used for the treatment of D1 mediation (or D1 is correlated with), it comprises and effectively regulates the compound of the formula I of the amount of (such as exciting or partial agonist) D1 (comprise its pharmacy acceptable salt, or the N-oxide compound of described compound or salt) to its Mammals (such as people) administration of needs.
The compound being used for the treatment of the formula I of the illness of D1 mediation also comprises the pharmacy acceptable salt of its N-oxide compound or described compound or described N-oxide compound.
The illness of D1 mediation (or D1 is correlated with) comprises nervous disorders [such as tourette's syndrome, tardive dyskinesia, Parkinson's disease (comprising such as relevant to PD cognitive impairment), cognitive disorder { comprises amnesia, the cognition decline that age is relevant, dull-witted [such as senile dementia, the dementia that alzheimer's disease is relevant, the dementia that HIV is relevant, the dementia that huntington disease is relevant, Lewy body is dull-witted, vascular dementia, volume temporal lobe type is dull-witted, the dementia (such as relevant to pharmacotherapy (such as D2 antagonist therapy) dementia) that medicine is relevant], delirium and cognitive impairment (such as relevant to AD cognitive impairment or the cognitive impairment relevant with PD) and mild cognitive impairment }, Huntington chorea/disease, and restless leg syndrome (RLS)], mental illness [such as cognitive impairment (such as relevant to schizophrenia cognitive impairment or the cognitive impairment relevant with pharmacotherapy (such as D2 antagonist therapy)), anxiety (comprising acute stress disorder, generalized anxiety disorder, social anxiety disorder, terrified disease, posttraumatic stress disorder and obsession), factitious disorder (comprising acute hallucinatory mania disease), impulse control disorder/impulsion (comprising compulsive gambling and intermittent explosive disorder), mood disorder (comprises I type bipolar disorder, II type bipolar disorder, mania, mixed feeling state (mixed affective state), dysthymia disorders { dysthymia disorders that such as age is relevant, major depression, chronic depression, seasonal depression disease, psychotic depression, post-natal depression and refractory depression (TRD) }, psychomotor activity (psychomotor) illness, mental disorder [comprising schizophrenia (comprising the cognitive symptom in such as schizophrenia and negative symptom), schizoaffective disorders, Schizophreniform and paranoea], substance abuse and pharmacological dependence (comprising narcotic dependence, alcoholism, amphetamine dependence, cocaine habituation, nicotine dependence and abstinence syndrome from drugs), drug abuse recurrence, eating disorder (comprising anorexia, exessive appetite, disease of eating too much at one meal, excessive eating, hyperphagia and pagophagia), autism spectrum disorder (such as autism), chronic apathy, anhedonia, confirmed fatigue, seasonal affective disorder and paediatrics mental illness (comprise attention deficit disorder, attention deficit hyperactivity disorder (ADHD), conduct disorder and autism)], endocrine disorder (such as hyperprolactinemia) or other illness, comprise drowsiness, excess daytime somnolence, emaciation, absent minded, sexual dysfunction (such as erective dysfunction, sexual dysfunction after SSRI), pain, migraine, systemic lupus erythematous (SLE), hyperglycemia, atherosclerosis, hyperlipemia, obesity, diabetes, septicemia, post-ischemic renal tubular necrosis, renal failure, hyponatremia, refractory edema, narcolepsy, cardiovascular disorder (such as hypertension), congestive heart failure, Post operation eye tension force is too low, somnopathy and serotonin syndrome.
Another embodiment of the present invention is provided for the method for the following illness for the treatment of Mammals (such as people), and described illness is nervous disorders [such as tourette's syndrome; Tardive dyskinesia; Parkinson's disease; Cognitive disorder comprise amnesia, dementia that dementia that dementia that senile dementia, HIV are correlated with, alzheimer's disease are correlated with, huntington disease are correlated with, Lewy body dementia, vascular dementia, dementia (such as relevant to D2 antagonist therapy cognitive impairment), delirium and mild cognitive impairment that medicine is relevant); RLS and Huntington chorea/disease], mental illness [such as anxiety (comprising acute stress disorder, generalized anxiety disorder, social anxiety disorder, terrified sick, posttraumatic stress disorder and obsession); Factitious disorder (comprising acute hallucinatory mania disease); Impulse control disorder/impulsion (comprising compulsive gambling and intermittent explosive disorder); Mood disorder (comprising I type bipolar disorder, II type bipolar disorder, mania, mixed feeling state, major depression, chronic depression, seasonal depression disease, psychotic depression and post-natal depression); Psychomotor activity illness; Mental disorder (comprising schizophrenia, schizoaffective disorders, Schizophreniform and paranoea); Pharmacological dependence (comprising narcotic dependence, alcoholism, amphetamine dependence, cocaine habituation, nicotine dependence and abstinence syndrome from drugs); Eating disorder (comprising anorexia, exessive appetite, disease of eating too much at one meal, hyperphagia and pagophagia); And paediatrics mental illness (comprising attention deficit disorder, attention deficit hyperactivity disorder obstacle, conduct disorder and autism)] or endocrine disorder (such as hyperprolactinemia), described method comprises the compound of the formula I to described Mammals drug treatment significant quantity.
Another embodiment of the present invention comprises the method for the illness being used for the treatment of Mammals (such as people), described method comprises the compound of the formula I to described Mammals drug treatment significant quantity, and wherein said illness is selected from schizophrenia (the cognitive symptom in such as schizophrenia and negative symptom), cognitive impairment [such as relevant to schizophrenia cognitive impairment, the cognitive impairment relevant to AD, the cognitive impairment relevant to PD, the cognitive impairment relevant to pharmacotherapy (such as D2 antagonist therapy) and mild cognitive impairment], attention deficit hyperactivity disorder (ADHD), impulsion, compulsive gambling, eating disorder (such as anorexia, exessive appetite, disease of eating too much at one meal, excessive eating, hyperphagia and pagophagia), autism spectrum disorder, mild cognitive impairment (MCI), the cognition decline that age is relevant, dull-witted (such as senile dementia, the dementia that HIV is relevant, Alzheimer, Lewy body is dull-witted, vascular dementia or volume temporal lobe type dementia), restless leg syndrome (RLS), Parkinson's disease, Huntington chorea, anxiety, dysthymia disorders (dysthymia disorders that such as age is relevant), major depressive disorder (MDD), refractory depression (TRD), bipolar disorder, chronic apathy, anhedonia, confirmed fatigue, posttraumatic stress disorder, seasonal affective disorder, social anxiety disorder, post-natal depression, serotonin syndrome, substance abuse and pharmacological dependence, drug abuse is recurred, tourette's syndrome, tardive dyskinesia, drowsiness, excess daytime somnolence, emaciation, absent minded, sexual dysfunction (after such as erective dysfunction or SSRI sexual dysfunction), migraine, systemic lupus erythematous (SLE), hyperglycemia, atherosclerosis, hyperlipemia, obesity, diabetes, septicemia, post-ischemic renal tubular necrosis, renal failure, hyponatremia, refractory edema, narcolepsy, hypertension, congestive heart failure, Post operation eye tension force is too low, somnopathy and pain.
Another embodiment of the present invention comprises the schizophrenia (the cognitive symptom in such as schizophrenia and negative symptom or the cognitive impairment relevant to schizophrenia) or psychotic method that are used for the treatment of Mammals (such as people), and described method comprises the compound of the formula I to described Mammals (such as people) drug treatment significant quantity.
Another embodiment of the present invention comprises the method for the schizophrenia (the cognitive symptom in such as schizophrenia and negative symptom or the cognitive impairment relevant to schizophrenia) being used for the treatment of Mammals (such as people), and described method comprises the compound of the formula I to described Mammals drug treatment significant quantity.
Another embodiment of the present invention comprises the method for the cognitive impairment [such as relevant to schizophrenia cognitive impairment, the cognitive impairment of being correlated with AD or the cognitive impairment relevant with PD] being used for the treatment of Mammals (such as people), and described method comprises the compound of the formula I to described Mammals drug treatment significant quantity.
Another embodiment of the present invention comprise be used for the treatment of Mammals (such as people) AD (such as treatment cognitive impairment) relevant to AD, PD (cognitive impairment that such as treatment and PD are correlated with), RLS, dysthymia disorders or MDD method, described method comprises the compound of the formula I to described Mammals drug treatment significant quantity.
As used herein, the term " treatment significant quantity " refer to be alleviated to a certain extent after administration the amount of compound (comprise its pharmacy acceptable salt, or the N-oxide compound of described compound or salt) of one or more symptom sanatory.For the treatment of illness (such as schizophrenia) of D1 mediation, treatment significant quantity refers to effectively to alleviate to a certain extent the amount of one or more relevant symptom of (or such as eliminating) and the illness that D1 mediates (the cognitive symptom in such as schizophrenia or schizophrenia and negative symptom or the cognitive impairment relevant with schizophrenia).
Unless otherwise indicated, otherwise as used herein, term " treatment (treating) " means to reverse, alleviate, the progress of one or more symptom of the illness that suppresses such term to be applied or the patient's condition or such illness or the patient's condition, or prevents one or more symptom of such illness or the patient's condition or such illness or the patient's condition.Unless otherwise indicated, otherwise as used herein, term " treatment (treatment) " refers to as herein defined the treatment behavior of " treatment (treating) ".Term " treatment " also comprises the auxiliary of individuality and lower rectal cancer.
The administration of the compound of formula I is by making it possible to any method of compound delivery to site of action to realize.These methods comprise oral route, intra-nasal route, inhalation route, intraduodenal route, parenteral injection (comprising intravenously, subcutaneous, intramuscular, Ink vessel transfusing or infusion), local and rectal administration.
In one embodiment of the invention, the compound of formula I can carry out administration/realization by oral route.
Adjustable dosage regimen is to provide best required response.Such as, can administration single bolus, can the several divided dose of administration in time, or can as treat situation urgent need as indicated in and reduce in proportion or increase dosage.It is useful for parenteral composition being formulated as unit dosage form to be easy to administration and to make dosage homogeneous.As used herein, unit dosage form refers to be applicable to the physical discrete unit of integral dose for mammalian subject to be treated; Each unit all containing after combining with required pharmaceutical carrier through calculating the active compound of the predetermined amount to produce required result for the treatment of.The specification of unit dosage form of the present invention is arranged by many factors, the specific characteristic of such as therapeutical agent and the particular treatment that will obtain or preventive effect.In one embodiment of the invention, the compound of formula I can be used for treating people.
It should be noted that dose value can change with the type of the patient's condition that will alleviate and seriousness, and single or multiple dosage can be comprised.To understand further; for any particular individual; concrete dosage regimen should adjust in time according to the professional judgement of the personnel of the administration of individual need and administration composition or supervision group compound; and set forth dosage range is only exemplary, be not intended the scope or the practice that limit claimed composition herein.Such as, can adjust dosage based on pharmacokinetics or pharmacodynamic parameter, described parameter can comprise clinical effectiveness, such as toxic effect and/or experimental value.Therefore, Intra-patient dose escalation as determined in those skilled in the art is contained in the present invention.Determine that the suitable dosage of administration chemotherapeutic and scheme are known in association area, and once provide instruction disclosed herein, then it will be understood by those skilled in the art that described suitable dosage and scheme are covered by wherein.
The amount of the compound of the formula I of institute's administration can depend on the judgement of the seriousness of treated individuality, illness or the patient's condition, the speed of administration, the disposal of compound and prescriber.Generally speaking, effective dose every day every kg body weight about 0.0001 to about 50mg, such as about 0.01 to about 10mg/kg/ day (single or divided doses).For the people of 70kg, this can add up to about 0.007mg/ day to about 3500mg/ day, such as about 0.7mg/ day to about 700mg/ day.In some cases, dosage level lower than the lower limit of aforementioned range can be enough, and in other cases, larger dose still can be adopted when not causing any harmful side effect, condition first described larger dose is divided into several smaller dose with administration in a whole day.
As used herein, term " combination treatment " refers to the compound of formula I and the extra medicine of at least one or medicament (such as antischizophrinic agent) order or administration simultaneously.
The present invention includes the purposes of the compound of formula I and the combination of one or more extra pharmaceutically active agents.If the combination of administration promoting agent, then the formulation that can separate of described promoting agent or with the form combined in single formulation order or administration simultaneously.Correspondingly, the present invention also comprises pharmaceutical composition, and it comprises a certain amount of: (a) first medicament, the compound (comprising the pharmacy acceptable salt of its N-oxide compound or described compound or described N-oxide compound) of its contained I; (b) second pharmaceutically active agents; And (c) pharmaceutically acceptable carrier, vehicle or thinner.
According to the disease that will treat, illness or the patient's condition, choosing multiple pharmaceutically active agents is to be combined with the compound of formula I.The pharmaceutically active agents that can use with combination of compositions of the present invention includes, but is not limited to:
(i) acetylcholinesterase depressant, such as E 2020 (ARICEPT, MEMAC); Or adenosine A 2Areceptor antagonist, such as Pu Ruidingnai (SCH 420814) or SCH 412348;
(ii) amyloid-β (or its fragment), the A β such as puted together with the epi-position (PADRE) in conjunction with pan HLA DR 1-15, and ACC-001 (Elan/Wyeth);
(iii) antibody of amyloid-β (or its fragment), such as clings to a pearl monoclonal antibody (being also called AAB-001) and AAB-002 (Wyeth/Elan);
(iv) amyloid reduce or inhibitor (comprise reduce amyloid produce, accumulation and Fibrotic those), such as colostrinin and bisnorcymserine (being also called BNC);
(v) alpha adrenergic receptor agonists, such as clonidine (CATAPRES);
(vi) B-adrenergic receptor blocker (beta-Blocking agent), such as carteolol;
(vii) anticholinergic, such as amitriptyline (ELAVIL, ENDEP);
(viii) anticonvulsive drug, such as Carbamzepine (TEGRETOL, CARBATROL);
(ix) antipsychotic drug, such as Lurasidone (is also called SM-13496; DainipponSumitomo);
(x) calcium channel blocker, such as nilvadipine (ESCOR, NIVADIL);
(xi) Catechol O-methyltransferase (COMT) inhibitor, such as tolcapone (TASMAR);
(xii) central nervous system stimulant, such as caffeine;
(xiii) reflunomide, such as prednisone (STERAPRED, DELTASONE);
(xiv) dopamine-receptor stimulant, such as Apomorphine (APOKYN);
(xv) dopamine-receptor antagonist, such as tetrabenazine (the dopamine D 2 antagonist of NITOMAN, XENAZINE, such as Quetiapine);
(xvi) dopamine reuptalce inhibitor, such as maleic acid nomifensine (MERITAL);
(xvii) γ-aminobutyric acid (GABA) receptor stimulant, such as baclofen (LIORESAL, KEMSTRO);
(xviii) histamine 3 (H 3) antagonist, such as ciproxifan;
(xix) immunomodulator, such as GA (is also called copolymer-1; COPAXONE);
(xx) immunosuppressor, such as methotrexate (TREXALL, RHEUMATREX);
(xxi) Interferon, rabbit, comprises interferon beta-1a (AVONEX, REBIF) and interferon beta-1b (BETASERON, BETAFERON);
(xxii) levodopa (or its methyl esters or ethyl ester), separately or combine with DOPA decarboxylase inhibitor (such as carbidopa (SINEMET, CARBILEV, PARCOPA));
(xxiii) N-methyl-D-aspartate (NMDA) receptor antagonist, such as memantine (NAMENDA, AXURA, EBIXA);
(xxiv) monoamine oxidase (MAO) inhibitor, such as selegiline (EMSAM);
(xxv) muscarinic receptor (especially M1 hypotype) agonist, such as urethan of .beta.-methylcholine chloride (DUVOID, URECHOLINE);
(xxvi) neuroprotective drug, such as 2,3,4,9-tetrahydrochysene-1H-carbazole-3-ketoximes;
(xxvii) nicotinic receptor agonists, such as epibatidine;
(xxviii) norepinephrine (norepinephrine/noradrenaline) reuptake inhibitor, such as tomoxetine (STRATTERA);
(xxix) phosphodiesterase (PDE) inhibitor, such as PDE9 inhibitor, such as BAY 73-6691 (Bayer AG) and PDE 10 (such as PDE10A) inhibitor, such as Papaverine;
(xxx) other PDE inhibitor, it comprises (a) PDE1 inhibitor (such as vinpocetin), (b) PDE2 inhibitor (such as red-9-(2-hydroxyl-3-nonyl) VITAMIN B4 (EHNA)), (c) PDE4 inhibitor (such as rolipram), and (d) PDE5 inhibitor (such as Virga (VIAGRA, REVATIO));
(xxxi) quinoline, such as quinine (comprising its hydrochloride, dihydrochloride, vitriol, hydrosulfate and gluconate);
(xxxii) beta-secretase inhibitor, such as WY-25105;
(xxxiii) inhibitors of gamma-secretase, such as LY-411575 (Lilly);
(xxxiv) thrombotonin (serotonin) 1A (5-HT 1A) receptor antagonist, such as spiperone;
(xxxv) thrombotonin (serotonin) 4 (5-HT 4) receptor stimulant, such as PRX-03140 (Epix);
(xxxvi) thrombotonin (serotonin) 6 (5-HT 6) receptor antagonist, such as mianserin (TORVOL, BOLVIDON, NORVAL);
(xxxvii) thrombotonin (5-HT) reuptake inhibitor, such as alaproclate, citalopram (CELEXA, CIPRAMIL);
(xxxviii) nutritional factor, such as nerve growth factor (NGF), Prostatropin (bFGF; ERSOFERMIN), neurotrophic factor-3 (NT-3), cardiotrophin-1, Brain Derived Neurotrophic Factor (BDNF), schwann's sheath embryonin, nickel line albumen and glial cell derived neurotrophic factor (GDNF), and the medicament stimulating nutritional factor to produce, such as propentofylline;
Deng.
The compound of formula I optionally combinationally uses with another kind of promoting agent.Such promoting agent can be such as atypical antipsychotic agent or Mirapexin agent or anti-Alzheimer disease medicament.Correspondingly, another embodiment of the present invention provides the method for the illness (such as relevant to D1 nerve and mental illness) for the treatment of D1 mediation, it comprises the compound (comprising the pharmacy acceptable salt of its N-oxide compound or described compound or described N-oxide compound) of the formula I to Mammals effective dosage, and also comprises the another kind of promoting agent of administration.
As used herein, term " another kind of promoting agent " refers to any therapeutical agent of can be used for treating except the compound except formula I (comprising the pharmacy acceptable salt of its N-oxide compound or described compound or described N-oxide compound) of individual illness.The example of additional therapeutic agent comprises thymoleptic, antipsychotic (such as antipsychotic) medicine, anti-pain agent, Mirapexin agent, anti-LID (dyskinesia of levodopa induction) agent, anti-Alzheimer disease medicament and antianxiety agent.The example of the thymoleptic of the particular category that can use with compound combination of the present invention comprises norepinephrine reuptake inhibitor, selective serotonin reuptake inhibitor (SSRI), nk 1 receptor antagonist, oxidase inhibitor (MAOI), the reversible inhibitor (RIMA) of monoamine oxidase, thrombotonin and norepinephrine reuptake inhibitor (SNRI), corticotropin releasing factor (CRF) (CRF) antagonist, alpha-adrenergic aceptor antagonist and atypical antidepressants.The norepinephrine reuptake inhibitor be applicable to comprises tertiary amine three ring medicine and secondary amine three ring medicine.The tertiary amine three ring medicine be applicable to and the example of secondary amine three ring medicine comprise amitriptyline, clomipramine, doxepin, imipramine, Trimipramine, dothiepin, butriptyline, iprindole, Tymelvt, nortriptyline, protriptyline, amoxapine, Desipramine and maprotiline.The example of the selective serotonin reuptake inhibitor be applicable to comprises fluoxetine, fluvoxamine, paroxetine and Sertraline.The example of oxidase inhibitor comprises Isocarboxazid, Phenelzine and tranylcyclopramine.The example of the reversible inhibitor of the monoamine oxidase be applicable to comprises moclobemide.The example being suitable for thrombotonin in the present invention and norepinephrine reuptake inhibitor comprises Venlafaxine.The example of the atypical antidepressants be applicable to comprises Bupropion, lithium, nefazodone, trazodone and viloxazine.The example of anti-Alzheimer disease medicament comprises Dimebon, nmda receptor antagonist (such as memantine) and anticholinesterase (such as E2020 and lycoremine).The example of the antianxiety agent of the applicable classification that can use with compound combination of the present invention comprises benzodiazepine and thrombotonin 1A (5-HT1A) agonist or antagonist (particularly 5-HT1A partial agonist), and corticotropin releasing factor (CRF) (CRF) antagonist.The benzodiazepine be applicable to comprise alprazolam, chlorine nitrogen , clonazepam, chloramines butyl ester, stable, halazepam, lorazepam, oxazepam and prazepam.It is grand that the 5-HT1A receptor stimulant be applicable to or antagonist comprise fourth spiral shell ketone, flesinoxan, gepirone and her thatch.The atypical antipsychotic agents be applicable to comprises 9-hydroxy-risperidone, bifeprunox, Ziprasidone, risperidone, Aripiprazole, olanzapine and Quetiapine.The nicotinic acetycholine agonist be applicable to comprises isopropyl Crane, varenicline and MEM3454.Anti-pain agent comprises lyrica, gabapentin, clonidine, prostigmin(e), baclofen, midazolam, ketamine and ziconotide.The example of Mirapexin agent be applicable to comprises L-DOPA (or its methyl esters or ethyl ester), DOPA decarboxylase inhibitor (such as carbidopa (SINEMET, CARBILEV, PARCOPA), adenosine A 2Areceptor antagonist [such as Pu Ruidingnai (SCH 420814) or SCH 412348], benserazide (MADOPAR), alpha-methyldopa, single methyl fluoride DOPA, difluoromethyl DOPA, brocresine or a hydroxyl benzyl hydrazine), dopamine agonist [such as Apomorphine (APOKYN), bromocriptine (PARLODEL), Cabergoline (DOSTINEX), D1 receptor stimulant (dihydrexidine), dihydroergocryptine, Fenoldopam (CORLOPAM), lisuride (DOPERGIN), Pei Gaolai (PERMAX), Piribedil (TRIVASTAL, TRASTAL), pramipexole (MIRAPEX), quinpirole, Ropinirole (REQUIP), INN (NEUPRO), SKF-82958 (GlaxoSmithKline) and sarizotan], monoamine oxidase (MAO) inhibitor [such as selegiline (EMSAM), SelegilineHydrochloride (L-selegiline (L-deprenyl), ELDEPRYL, ZELAPAR), dimethyl selegiline (dimethylselegilene), brofaromine, Phenelzine (NARDIL), Tranylcypromine (PARNATE), moclobemide (AURORIX, MANERIX), befloxatone, husky non-amine, Isocarboxazid (MARPLAN), nialamide (NIAMID), rasagiline (AZILECT), IIH (MARSILID, IPROZID, IPRONID), CHF-3381 (Chiesi Farmaceutici), iproclozide, Toloxatone (HUMORYL, PERENUM), bifemelane, deoxypeganine (desoxypeganine), yajeine (being also called banisterine or banasterine), Ha Maling, Linezolid (ZYVOX, and Pargyline (EUDATIN ZYVOXID), SUPIRDYL)], Catechol O-methyltransferase (COMT) inhibitor [such as tolcapone (TASMAR), Entacapone (COMTAN) and tropolone], N-methyl-D-aspartate (NMDA) receptor antagonist [such as amantadine (SYMMETREL)], anticholinergic [such as amitriptyline (ELAVIL, ENDEP), butriptyline, benztropine mesylate (COGENTIN), Trihexyphenidyl (ARTANE), diphenhydramine (BENADRYL), orphenadrine (NORFLEX), Daturine, coromegine (ATROPEN), scopolamine (TRANSDERM-SCOP), Scopolate (PARMINE), Dicycloverine (BENTYL, BYCLOMINE, DIBENT, DILOMINE, tolterodine (DETROL), Oxybutynin (DITROPAN, LYRINEL XL, OXYTROL), Penthienate Bromide, Propanthelinium (PRO-BANTHINE), cyclizine, Impamin (TOFRANIL), maleic acid imipramine (SURMONTIL), Tymelvt, Desipramine (NORPRAMIN), doxepin (SINEQUAN, ZONALON), Trimipramine (SURMONTIL) and Glycopyrronium Bromide (ROBINUL)] or its combination.The example of antischizophrinic agent comprises Ziprasidone, risperidone, olanzapine, Quetiapine, Aripiprazole, asenapine, blonanserin or Yi Luo piperazine ketone.
As mentioned above, the compound (comprising the pharmacy acceptable salt of its N-oxide compound and described compound or salt) of formula I can combinationally use with one or more extra antischizophrinic agent described herein.When using combination treatment, one or more extra antischizophrinic agent can with compound of the present invention order or administration simultaneously.In one embodiment, before administration compound of the present invention, to the extra antischizophrinic agent of Mammals (such as people) administration.In another embodiment, after administration compound of the present invention, to the extra antischizophrinic agent of Mammals administration.In another embodiment, while administration compound of the present invention (or its N-oxide compound or aforesaid pharmacy acceptable salt) to the extra antischizophrinic agent of Mammals (such as people) administration.
The present invention also provides pharmaceutical composition, it is used for the treatment of the schizophrenia of Mammals (comprising people), the compound (or its N-oxide compound or aforesaid pharmacy acceptable salt) that described pharmaceutical composition comprises a certain amount of formula I as hereinbefore defined (comprises the hydrate of described compound or its pharmacy acceptable salt, solvate and polymorphic form) and one or more (such as one to three kind) antischizophrinic agent (such as Ziprasidone, risperidone, olanzapine, Quetiapine, Aripiprazole, asenapine, blonanserin or Yi Luo piperazine ketone) combination, the amount of wherein said promoting agent and described combination when taking as a whole therapeutically effective to treating schizophrenia.
The present invention also provides pharmaceutical composition, it is used for the treatment of the Parkinson's disease (comprising the cognitive impairment relevant to PD) of Mammals (comprising people), the compound (or its N-oxide compound or aforesaid pharmacy acceptable salt) that described pharmaceutical composition comprises a certain amount of formula I as hereinbefore defined (comprises the hydrate of described compound or its pharmacy acceptable salt, solvate and polymorphic form) combine with one or more (such as one to three kind) Mirapexin agent (such as L-DOPA), the amount of wherein said promoting agent and described combination when taking as a whole therapeutically effective to treating Parkinson's disease.
The compound should understanding the formula I of above description is not limited to shown given enantiomer, and also comprises its all steric isomers and mixture.
Detailed Description Of The Invention
Compound of the present invention (comprising the salt of N-oxide compound and described compound or N-oxide compound) can use known organic synthesis technology to prepare, and can synthesize according to any one in a large amount of possibility synthetic route.
Reaction for the preparation of compound of the present invention can be carried out in the solvent be applicable to, and described solvent easily can be selected by the technician in organic synthesis field.The solvent be applicable to can not react with raw material (reactant), intermediate or product substantially reacting at the temperature (can temperature) in the scope of the temperature of solidification of solvent to the boiling temperature of solvent carried out.The reaction of specifying can be carried out in the mixture of a kind of solvent or more than one solvents.According to specific reactions steps, the solvent be applicable to for specific reactions steps can be selected by those skilled in the art.
The preparation of compound of the present invention can relate to protection and the deprotection of number of chemical group.For protection and the demand of deprotection, and select suitable protecting group easily can be determined by those skilled in the art.Protecting group chemistry is found in such as T.W.Greene and P.G.M.Wuts, Protective Groups inOrganic Synthesis, the 3rd edition; Wiley & Sons; Inc., in New York (1999), it is quoted with its entirety and adds herein.
Reaction can be monitored according to any applicable method as known in the art.Such as, by spectrum means, (such as nuclear magnetic resonance spectrometry (such as in product formation 1h or 13c), infrared spectroscopy, spectrophotometry (such as UV-is visible), mass spectrum) or monitored by chromatographic process (such as high performance liquid chromatography (HPLC) or tlc (TLC)).
The compound of formula I and intermediate thereof can be prepared according to following reaction scheme and discussion of enclosing.Unless otherwise indicated, otherwise reaction scheme and subsequently discuss in R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, T 1, T 2, T 3, Q 1and X 1, and structural formula I all as hereinbefore defined.Generally speaking, compound of the present invention, by comprising the method with known those similar methods in chemical field, particularly obtains according to description comprised herein.Some method for the preparation of compound of the present invention and intermediate thereof provides as further feature of the present invention, and is illustrated by following reaction scheme.Other method is described in experimental section.The route provided herein and embodiment (comprising corresponding description) only for illustration of, be not intended to limit the scope of the invention.
Route 1 refers to the preparation of the compound of formula I.With reference to compound [the wherein Lg of route 1, formula 1-1 1for the leavings group be applicable to, such as halo (such as Cl or Br); And Pg 1for the protecting group be applicable to, such as tertbutyloxycarbonyl (Boc), [2-(TMS) oxyethyl group] methyl (SEM) or 2-THP trtrahydropyranyl (THP)] and compound [the wherein Z of formula 1-2 1for halogen (Cl, Br or I)] for commercially available, or obtain by method described herein or other method well known to those skilled in the art.The compound of formula 1-3 by by the compound of the compound of formula 1-1 and formula 1-2 under the suitable conditions coupling prepare.Described coupling can such as be passed through at alkali (such as Cs 2cO 3) in suitable solvent (such as DMSO), the mixture of the compound of heating-type 1-1 and the compound of formula 1-2 realizes under existence.Or, the coupling of metal catalytic (such as using palladium or copper catalyst) can be adopted to realize aforementioned coupling.In the version of this coupling, can at alkali (such as Cs 2cO 3), metal catalyst [such as palladium catalyst, such as [Pd (OAc) 2]) and under part (such as BINAP) exists, the mixture of the compound of heating-type 1-1 and the compound of formula 1-2 in the suitable solvent (such as Isosorbide-5-Nitrae-dioxane).Subsequently the compound of formula 1-3 can be passed through linked reaction and the formula Q of metal catalytic (such as using palladium catalyst) 1-Z 2compound [wherein Z 2can be Br; B (OH) 2; B (OR) 2, wherein each R is H or C all independently 1-6alkyl, or formed optionally by one or more C together with the B atom that wherein two (OR) groups connect with them 1-65 yuan to the 10 yuan Heterocyclylalkyls that alkyl replaces or heteroaryl; Trialkyltin groups; Deng] react with the compound obtaining formula I.Formula Q 1-Z 2compound be commercially available, or to prepare by method described herein or by those the method be similar to described in chemical field.Or, can be compound (the wherein Z of formula 1-4 by the converting compounds of formula 1-3 2as defined above).Such as, can by the compound of formula 1-3 (wherein Z 1for halogen, such as Br) compound [the wherein Z of formula 1-4 is converted into by method described herein or other method well known to those skilled in the art 2for B (OH) 2; B (OR) 2, wherein each R is H or C all independently 1-6alkyl, or formed optionally by one or more C together with the B atom that wherein two (OR) groups connect with them 1-65 yuan to the 10 yuan Heterocyclylalkyls that alkyl replaces or heteroaryl].In this embodiment, this reaction can such as be passed through compound (the wherein Z of formula 1-3 in the solvent (such as Isosorbide-5-Nitrae-dioxane) be applicable to 1for halogen, such as Br) with 4,4,4', 4', 5,5,5', 5'-prestox-2,2'-two-1,3,2-dioxa boron penta ring, applicable alkali (such as potassium acetate) and palladium catalyst { such as [two (diphenylphosphino) ferrocene of 1,1'-] palladium chloride (II) } reaction realize.In another embodiment, can by the compound of formula 1-3 (wherein Z 1for halogen, such as Br) compound (the wherein Z of formula 1-4 is converted into by other selective method described herein or other method well known to those skilled in the art 2for trialkyltin groups).In this embodiment, this reaction can such as by palladium catalyst [such as tetrakis triphenylphosphine palladium (0)] exist under in be applicable to solvent (such as Isosorbide-5-Nitrae-dioxane) in by compound (the wherein Z of formula 1-3 1for halogen, such as Br) react to realize with six alkyl two stannanes (such as hexa methyl ditin alkane).Then the linked reaction of the compound of formula 1-4 by metal catalytic (such as using palladium catalyst) can be come and formula Q 1-Z 1compound (wherein Z 1as defined above) reaction is with the compound obtaining formula I.Formula Q 1-Z 1compound be commercially available, or to prepare by method described herein or by those the method be similar to described in chemical field.The reaction type adopted depends on selected Z 1and Z 2.Such as, Z is worked as 1for halogen or triflate and Q 1-Z 2reagent be boric acid or boric acid ester time, can use Suzuki react [A.Suzuki, J.Organomet.Chem.1999,576,147-168; N.Miyaura and A.Suzuki, Chem.Rev.1995,95,2457-2483; The people such as A.F.Littke, J.Am.Chem.Soc.2000,122,4020-4028].In some specific embodiments, by the aromatic iodide of formula 1-3, bromide or triflate be applicable to organic solvent (such as tetrahydrofuran (THF) (THF)) in formula Q 1-Z 2aryl or heteroaryl-boronic acids or boric acid ester and applicable alkali (such as potassiumphosphate) merge.Add palladium catalyst, such as S-Phos procatalyst (precatalyst) { is also called chlorine (2-dicyclohexyl phosphino--2', 6'-dimethoxy-1,1'-biphenyl) [2-(2-amino-ethyl phenyl)] palladium (II)-t-butyl methyl ether adducts }, and reacting by heating mixture.Or, work as Z 1for halogen or triflate and Z 2during for trialkyltin, Stille coupling [people such as V.Farina, Organic Reactions 1997,50,1-652] can be adopted.More specifically, can by the compound of formula 1-3 (wherein Z 1for bromide, iodide or triflate) under palladium catalyst (such as dichloro two (triphenyl phosphine) palladium (II)) exists in the organic solvent (such as toluene) be applicable to formula Q 1-Z 2compound (wherein Q 1-Z 2compound be Q 1stannane compound) merge, and can reacting by heating.Work as Z 1for Br, I or triflate and Z 2during for Br or I, Negishi coupling [E.Erdik, Tetrahedron 1992,48,9577-9648] can be used.More specifically, can by the compound of formula 1-3 (wherein Z 1for bromide, iodide or triflate) by suitable solvent (such as THF), at the temperature of-80 DEG C to-65 DEG C, with the alkyl lithium reagents of 1 to 1.1 equivalent, carry out metal transfer (transmetallate) by the solution-treated of 1.2 to 1.4 equivalent zinc chloride subsequently.Be warmed to 10 DEG C with the temperature of 30 DEG C after, available formula Q 1-Z 2compound (wherein Z 2for Br or I) reaction mixture, and heat at 50 DEG C to 70 DEG C when adding catalyzer (such as tetrakis triphenylphosphine palladium (0)).Reaction can be carried out within the time of 1 to 24 hour.Then the compound of formula 1-5 can be used and depend on Pg 1the felicity condition of the selection of group carrys out deprotection, to obtain the compound of formula I.These reactions are all not limited to use above-mentioned solvent, alkali, catalyzer or part, but can use other conditions many.
Route 1
Route 2 also refers to the preparation of the compound of formula I.Compound with reference to route 2, formula I can utilize those the chemical conversion be similar to described in route 1 to prepare, but step sequence is different.Compound [the wherein Pg of formula 2-1 2for the protecting group be applicable to, such as methyl, phenmethyl, THP or tri isopropyl silane base (TIPS)] for commercially available, or prepare by method described herein or other method well known to those skilled in the art.Can those the method be similar to described in route 1 be used to be converted into the compound of formula 2-2 the compound of formula 2-1, or after the compound being converted into formula 2-3, be converted into the compound of formula 2-2 again.Can use subsequently and depend on selected Pg 2the felicity condition of group, by the compound deprotection of formula 2-2, to obtain the compound of formula 2-4, by the compound coupling of the formula 1-1 in itself and route 1, can obtain the compound of formula 1-5 again.Described the those when coupling condition adopted can be similar to the compound of the preparation formula 1-3 in route 1.Then can use and depend on selected Pg 1the felicity condition of group, by the compound deprotection of formula 1-5, obtains the compound of formula I.
Route 2
Route 3 refers to compound (the wherein A of formula 3-3 1for Pg as hereinbefore defined 2or formula A 1agroup) preparation, described compound can be used as the intermediate/raw material of the compound of preparation formula I in route 2.Compound with reference to route 3, formula 3-1 is commercially available, or obtains by method described herein or other method well known to those skilled in the art.The compound of formula 3-1 and the chloro-3-nitropyridine of 4-can be reacted, and subsequently can by initial product reduction with the compound obtaining formula 3-2.The example of the reaction conditions be applicable to the coupling of 4-chloro-3-nitropyridine for the compound of formula 3-1 is included in applicable reaction solvent (such as ethanol) and is mixed with the alkali (such as triethylamine) be applicable to by two kinds of reactants.Subsequently by such as under catalyzer (such as palladium/carbon) exists in the solvent (such as methyl alcohol) be applicable to hydrogenation reduce nitro and obtain the compound of formula 3-2.The hydrogen pressure being applicable to previous reaction is generally 1atm to 4atm.Then the compound of formula 3-2 can be heated together with diacetyl oxide and triethyl orthoformate, obtain the compound of formula 3-3.
Route 3
Route 4 refers to compound (the wherein R of formula 4-4 or 4-5 9for such as C 1-3alkyl, such as methyl) preparation, this compound can be used as the intermediate/raw material of the compound of preparation formula I in route 2.Compound with reference to route 4, formula 4-1 is commercially available, or obtains by method described herein or other method well known to those skilled in the art.The aryl ketones of formula 4-1 and alkyl nitrite (such as Isopentyl nitrite) react to prepare by the compound of formula 4-2 under existing in acid (all example hydrochloric acids).The diketone being converted into formula 4-3 after lower formaldehyde (or its equivalent, such as metaformaldehyde or polyoxymethylene) processes can be there is in the oxime of the formula 4-2 of gained in acid (such as aqueous hydrochloric acid).The diketone of formula 4-3 can react with G-NH2 or its salt (such as acetate) under alkali (such as sodium hydroxide) exists, and obtains the pyrazinones of formula 4-4.By with alkali [such as LDA, LHMDS etc.] and formula R 11-Z 3compound [wherein Z 3for acceptable leavings group, such as Cl, Br, I, methanesulfonates etc., and wherein R 11for such as C 1-3alkyl (such as methyl)] process formula 4-4 compound make pyrazinones N-alkylation to obtain the compound of formula 4-5.The reaction solvent be applicable to can be selected from polar aprotic solvent, such as DMF (DMF), Isosorbide-5-Nitrae-dioxane or THF usually.
Route 4
Or the compound of formula 4-5 can as [wherein R in route 5 11for such as H or C 1-3alkyl (such as methyl)] be prepared, this compound can be used as the intermediate/raw material of the compound of preparation formula I in route 2.Compound with reference to route 5, formula 5-1 and 5-2 is commercially available, or obtains by method described herein or other method well known to those skilled in the art.The compound of formula 5-3 is by preparing the compound coupling of the compound of formula 5-1 and formula 5-2.The compound of the compound of formula 5-1 and formula 5-2 reacts to realize by aforementioned coupling under existing at the alkali (such as salt of wormwood) be applicable to, the catalyzer [such as tetrakis triphenylphosphine palladium (0)] of being applicable to and applicable solvent (such as ethanol).The compound of formula 5-3 can in solvent (such as methylene dichloride) with MALEIC ANHYDRIDE and hydroperoxidation to provide the compound of formula 5-4, this compound can comprise the mixture of N-oxide areas isomer.The compound of formula 5-5 can be prepared by heating together with diacetyl oxide from the compound of formula 5-4; This initial product can use alkali (such as NaOH) to carry out saponification in the polar solvent (such as water or methyl alcohol) be applicable to.The compound of formula 4-5 can from the compound of formula 5-5 by with the alkali (such as LDA, LHMDS etc.), lithiumbromide and the formula R that are applicable to 11-Z 3compound (wherein Z 3for acceptable leavings group, such as Cl, Br, I, methanesulfonates etc.) react and prepare.The reaction solvent be applicable to can be selected from polar aprotic solvent (such as DMF, Isosorbide-5-Nitrae-dioxane or THF) usually.
Route 5
Route 6 refers to compound [the wherein R of formula 6-6 yfor H or R 10(such as C 1-3alkyl, such as methyl), and Pg 3for be applicable to protecting group, such as THP] preparation, this compound can be used as the intermediate/raw material of the compound of preparation formula I in route 2.Compound with reference to route 6, formula 6-1 and 6-2 is commercially available, or obtains by method described herein or other method well known to those skilled in the art.The compound of formula 6-3 is by preparing the enol triflate coupling of the compound of formula 6-1 and formula 6-2.The triflate of the compound of formula 6-1 and formula 6-2 reacts to realize by aforementioned coupling under existing at the alkali (such as salt of wormwood) be applicable to, the catalyzer [such as acid chloride (II)] of being applicable to, the part (such as tricyclohexyl phosphine) be applicable to and the optional phase-transfer catalyst (such as tetrabutylammonium chloride) be applicable to.The reaction solvent be applicable to can be selected from polar aprotic solvent, such as Isosorbide-5-Nitrae-dioxane or THF usually.The compound of formula 6-3 can react with the alkali (such as DBU) be applicable to of 1 to 5 equivalent under oxygen atmosphere, obtains the compound of formula 6-4.The reaction solvent be applicable to can be selected from polar aprotic solvent, such as DMF, Isosorbide-5-Nitrae-dioxane or THF usually.The compound of formula 6-5 by obtaining the compound of formula 6-4 and hydrazine reaction in the solvent (such as n-butyl alcohol) be applicable to.The compound of formula 6-5 can use method described herein or other method well known to those skilled in the art to be converted into by the formula 6-6 compound suitably protected.
Route 6
Route 7 refers to compound [the wherein R of formula 7-6 yfor H or R 10(such as C 1-3alkyl, such as methyl)] preparation, this compound can be used as the intermediate/raw material of the compound of preparation formula I in route 2.Compound with reference to route 7, formula 7-1 and formula 7-2 is commercially available, or obtains by method described herein or other method well known to those skilled in the art.The compound of formula 7-3 is by compound [the wherein Pg by the compound of formula 7-1 and formula 7-2 4for the protecting group be applicable to, such as THP] prepared by coupling.Aforementioned coupling realizes by the compound of the compound and formula 7-2 that there is underfeed furnace 7-1 at the alkali (such as cesium carbonate) be applicable to and the catalyzer of being applicable to { such as [two (diphenylphosphino) ferrocene of 1,1'-] palladium chloride (II) }.The reaction solvent be applicable to can be selected from polar aprotic solvent, such as Isosorbide-5-Nitrae-dioxane or THF usually.The compound of formula 7-4 is by removing protecting group Pg 4obtain, such as, by compound (the wherein Pg with HCl process formula 7-3 in alcoholic solvent (such as 2-propyl alcohol) 4for such as THP).The compound of formula 7-5 can be provided with the compound of Phosphorus Oxychloride process formula 7-4 at elevated temperatures.The compound of formula 7-5 can be the reactive intermediate in the number of chemical conversion of acquisition formula 7-6 compound.Such as, the compound of formula 7-5 can react with trimethyl aluminium and applicable palladium catalyst [such as tetrakis triphenylphosphine palladium (0)] in Isosorbide-5-Nitrae-dioxane, obtains compound (the wherein new R introduced of formula 7-6 9for methyl).
Route 7
Route 8 refers to compound [the wherein R of formula 8-3 9for such as C 1-3alkyl (such as methyl); R 11for such as H or C 1-3alkyl (such as methyl); And Pg 5for the protecting group [such as SEM, Boc or benzyloxymethyl acetal (BOM)] be applicable to; A 2for H or Pg 2; And Pg 2for be applicable to protecting group (such as methoxymethyl (MOM) or phenmethyl)] preparation, this compound can be used as the intermediate/raw material of the compound of preparation formula I in route 2.Compound with reference to route 8, formula 8-1 and formula 8-2 is commercially available, or obtains by method described herein or other method well known to those skilled in the art.The compound of formula 8-3 is by preparing the compound coupling of the compound of formula 8-1 and formula 8-2.Aforementioned coupling realizes by the compound of the compound and formula 8-2 that there is underfeed furnace 8-1 at the alkali (such as salt of wormwood) be applicable to and the catalyzer of being applicable to { such as [two (diphenylphosphino) ferrocene of 1,1'-] palladium chloride (II) }.
Route 8
Or the compound of formula I is also prepared by the enzyme modification (such as microbiological oxidation) of the compound of relational expression I.Such as, as shown in route 9, in the buffer reagent be applicable to, hatch compound { such as, the wherein Q of formula I with pseudomonas putida (Pseudomonas putida) 1for oxidable group, all such as formula pyridazinyl [the wherein R be optionally substituted in the compound of 9-1 yfor H or R 10(such as C 1-3alkyl, such as methyl)] } continue compound (the such as wherein Q that reaction times of 24-96 hour can provide other selective formula I 1pyridazine ketone group for being optionally substituted in the compound of formula 9-2).
Route 9
Other raw material and the intermediate that can be used for preparing compound of the present invention can obtain from chemical retailer (such as Sigma-Aldrich), or can the method described in chemical field obtain.
One skilled in the art will recognize that, in all routes described in this article, such as, if there is functionality (reactivity) group (such as substituting group, R in a part for compound structure 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, Q 1deng), be then suitable for and/or method well known to those skilled in the art when needing, can be used to modify further.Such as ,-CN group can through hydrolysis to obtain amide group; Carboxylic acid can be converted into acid amides; Carboxylic acid can be converted into ester, and it again can through being reduced to alcohol, and this alcohol again can through further modification.In addition such as, OH group can be converted into better leavings group (such as methylsulfonic acid ester group), and it is suitable for again (such as by cryanide ion (CN -)) nucleophilic substitution.In addition such as ,-S-is oxidable is-S (=O)-and/or-S (=O) 2-.Again in addition such as, unsaturated link(age) (such as C=C or C ≡ C) is saturated bond by hydro-reduction.In some embodiments, primary amine or secondary amine group (are present in substituting group (such as R 3, R 4, R 9, R 10deng) on) by making itself and suitable reagent (such as acyl chlorides, SULPHURYL CHLORIDE, isocyanic ester or isothiocyanate compound) react to be converted into acid amides, sulphonamide, urea or thiourea group.One skilled in the art will realize that other such modification.Therefore, the compound with the substituent formula I comprising functional group can be converted into the compound of the other formula I with different substituents.
Similarly, those skilled in the art also can recognize, in all routes described in this article, if there is functionality (reactivity) group (such as R on substituting group 3, R 4, R 9, R 10deng), then suitable and/or when needing, in the synthetic route process described in this article, these functional groups can protected/deprotection.Such as, OH group can be protected by phenmethyl, methyl or ethanoyl, and it also can transform back OH group at building-up process later stage deprotection.In addition such as, NH 2group can by benzene methoxycarbonyl (Cbz) or Boc radical protection; It can transform back NH in the later stage of building-up process by deprotection 2group.
As used herein, term " reaction (reacting/reaction/reacted) " instigates specified chemical reactant to mix, to carry out chemical transformation to produce the compound different from any compound in initial drawing-in system.Reaction can be carried out in the presence or absence of a solvent.
The compound of formula I can the form of steric isomer (such as atropisomer, racemic modification, enantiomer or diastereomer) exist.The optical purity precursor that the routine techniques of the single enantiomer of preparation/separation comprises by being applicable to carries out chiral synthesize, or uses such as Chiral high pressure liquid phase chromatography (HPLC) to carry out resolution of racemates.Or, racemic modification (or racemize precursor) can react with the optically active compound (such as alcohol) be applicable to, or reacts with acid or alkali (such as tartrate or 1-phenylethylamine) when compound contains acidity or basic group.Gained diastereomeric mixtures is separated by chromatography and/or fractional crystallization, and will be converted into corresponding pure enantiomer in diastereomer one or both of by means well known to those skilled in the art.The chipal compounds (and chiral precurser) of formula I can use chromatography (being generally HPLC) to obtain with enantiotopic enriched form on asymmetric resin, and wherein moving phase is made up of hydrocarbon (being generally heptane or hexane) and contains 0% to 50% (usual 2% to 20%) 2-propyl alcohol and 0% to 5% alkylamine (usual 0.1% diethylamine).Concentrated eluate obtains the mixture of enrichment.Stereoisomerism agglomerated thing is separated by routine techniques well known by persons skilled in the art.See the Stereochemistry of Organic Compounds (Wiley, New York, 1994) of such as E.L.Eliel and S.H.Wilen, its content is quoted with its entirety and is added herein.The three-dimensional selection technique be applicable to is well known to those of ordinary skill in the art.
When the compound of formula I contains thiazolinyl or alkenylene (alkylidene group (alkylidene)), geometry cis/trans (or Z/E) isomer may be had.Cis/trans isomer is separated by routine techniques well known to those skilled in the art (such as chromatography and fractional crystallization).Salt of the present invention can be prepared according to method known to those skilled in the art.
The compound being essentially the formula I of alkalescence can form multiple salt with multiple mineral acid and organic acid.The salt of even now is pharmaceutically acceptable to being necessary for during animals administer, usually need first by the compound of the present invention that reaction mixture separation is the pharmaceutically form of unacceptable salt in practice, then by coming with alkaline reagents process the latter's (described pharmaceutically unacceptable salt) to be transformed back simply as free alkali compound, and subsequently latter free base is converted into pharmaceutically acceptable acid salt.The acid salt of basic cpd of the present invention by preparing with inorganic or this basic cpd of organic acid process in disease selected by equivalent in water solvent medium or in the organic solvent (such as methyl alcohol or ethanol) be applicable to.After evaporating solvent, obtain required solid salt.Required acid salt also precipitates by adding in solution described in suitable inorganic or organic acid cause in the solution of free alkali in organic solvent.
If compound of the present invention is alkali, then required pharmacy acceptable salt is prepared by any applicable method obtainable in this area, such as, process free alkali with mineral acid or organic acid, all example hydrochloric acids of described mineral acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc., described organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, FUMARIC ACID TECH GRADE, propanedioic acid, pyruvic acid, oxalic acid, oxyacetic acid, Whitfield's ointment, γ-picolinic acid, lactic acid, pantothenic acid, two tartrate (bitartric acid), xitix, DHB, glyconic acid, saccharic acid, formic acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, tosic acid and pamoic acid [i.e. 4,4'-methane two bases two (3-hydroxyl naphthalene-2-formic acid)], pyranosidyl acid (such as glucuronic acid or galacturonic acid), alpha hydroxy acid (such as citric acid or tartrate), amino acid (such as aspartic acid or L-glutamic acid), aromatic acid (such as phenylformic acid or styracin), sulfonic acid (such as ethyl sulfonic acid) etc.
The compound being essentially those acid formula I can form subsalt with multiple pharmacologically acceptable positively charged ion.The example of such salt comprises an alkali metal salt or alkaline earth salt, and particularly sodium and sylvite.These salt are all prepared by routine techniques.The chemical bases of reagent being used as preparation pharmaceutically acceptable subsalt of the present invention is and those of the compound formation non-toxic base salts of acid formula I.These salt are prepared by any applicable method, such as, process free acid with inorganic or organic bases, and described alkali is amine (primary amine, swollen amine or tertiary amine), alkali metal hydroxide or alkaline earth metal hydroxides etc. such as.These salt are also by with containing the corresponding acidic cpd of required pharmacologically acceptable cationic aqueous solution process, and then gained solution evaporation is prepared to drying by (such as under reduced pressure).Or then gained solution evaporation also by the lower alkanolic solutions of acidic cpd and required alkali metal alcoholates being mixed, and is prepared to drying by the same way as previously.In either case, use stoichiometric reagent to guarantee to react completely and the yield of required final product is the highest.
The pharmacy acceptable salt of the compound (comprising the compound of formula Ia or formula Ib) of formula I is prepared by one or more in three kinds of methods:
I () is by by the compound of formula I and required acid or alkali reaction;
(ii) by the acid needed for using or alkali, by the acid of the applicable precursor of the compound of formula I, unstable or alkali unstable protection base removes, or by cyclic precursor (such as lactone or lactan) open loop that the acid needed for using or alkali will be applicable to; Or
(iii) by a kind of salt of the compound of formula I being converted into another kind of salt with suitable acid or alkali reaction or by the ion exchange column be applicable to.
All three kinds of reactions are carried out all usually in the solution.Gained salt precipitable go out and collect by filtering, or to reclaim by evaporating solvent.The degree of ionization of gained salt can change to almost non-ionic scope in complete ionization.
Polymorphic form can be prepared according to technology well known to those skilled in the art (such as passing through crystallization).
When any racemate crystallises, the crystal that two kinds dissimilar may be had.The first type is racemic compound referred to above (real racemic modification), wherein produces the crystal of a kind of homogeneous form of two kinds of enantiomers containing equimolar amount.The second type is racemic mixture or agglomerated thing, wherein produces the crystal of two kinds of forms of each self-contained single enantiomer of equimolar amount.
The two kinds of crystalline forms be present in racemic mixture can have almost identical physical property, but it can have physical propertys different compared with real racemic modification.Racemic mixture by routine techniques well known by persons skilled in the art be separated-see the Stereochemistry of Organic Compounds (Wiley, New York, 1994) of such as E.L.Eliel and S.H.Wilen.
The present invention also comprises the compound of isotope-labeled formula I, and wherein one or more atom is by having same atoms ordinal number but atomic mass or the total mass number atomic mass common from occurring in nature or the different atom of total mass number are replaced.The compound of isotope-labeled formula I (or its pharmacy acceptable salt or its N-oxide compound) usually by routine techniques well known by persons skilled in the art or by being similar to those method described herein, using and replacing the unlabelled reagent used in other cases to prepare through suitable isotope-labeled reagent.
Prodrug of the present invention can such as by producing with the suitable functional group that some group well known by persons skilled in the art (" fore portion " such as described in the Design of Prodrugs (Elsevier, 1985) of H.Bundgaard) comes to exist in the compound of alternate form I.
The biological medicine characteristic (such as solubleness and stability of solution (across pH), rate of permeation etc.) of the compound of formula I should be assessed, think that indication that treatment advises is to select optimal formulation and route of administration.
The compound of the present invention being intended for pharmaceutical applications can the form administration of crystallization or amorphous products.Its method by such as precipitation, crystallization, lyophilize, spraying dry or evaporation drying obtains with such as solid plug, powder or form of film.Microwave or radio-frequency seasoning can be used for this object.
Can be individually dosed by it, or with one or more other compound combination administration of the present invention, or with one or more other medicines (or with its any array configuration) combination medicine-feeding.Generally speaking, can by it with dosage form and one or more pharmaceutically acceptable vehicle Combined Preparation.Term " vehicle " is in this article for describing any composition except compound of the present invention.The selection of vehicle to a great extent can depending on such as specific administration pattern, vehicle to the effect of solvability and stability and formulation qualitative factor.
Be suitable for pharmaceutical composition sending compound of the present invention (or its pharmacy acceptable salt) and preparation method thereof to those skilled in the art for apparent.Described composition and method of making the same is found in such as Remington's Pharmaceutical Sciences, in the 19th edition (Mack PublishingCompany, 1995).
Compound of the present invention (comprising its pharmacy acceptable salt and N-oxide compound thereof) can oral administration.Oral administration can relate to be swallowed, and enters gi tract to make compound; And/or containing taking, through tongue or sublingual administration, making compound directly enter blood flow from mouth thus.
The preparation being suitable for oral administration comprises solid, semisolid and liquid system, such as tablet; Soft capsule containing many particles or nano particle, liquid or powder or hard capsule; Lozenge (comprising liquid filling); Masticatory (chew); Gelifying agent; Fast dispersing dosage form; Membrane agent; Avette dose (ovule); Sprays; And containing docile dose/mucous membrane adhesion patch.
Liquid preparation comprises suspensoid, solution, syrup and elixir.Such preparation can the weighting agent form in soft capsule or hard capsule (such as being obtained by gelatin or Vltra tears) use, and usually comprises carrier (such as water, ethanol, polyoxyethylene glycol, propylene glycol, methylcellulose gum or applicable oil) and one or more emulsifying agent and/or suspending agent.Also (such as from anther sac) solid restores and prepares liquid preparation by making.
Compound of the present invention can also rapid solution, rapidly disintegrating dosage form use, such as by those described in the Expert Opinion in Therapeutic Patents 2001,11,981-986 of Liang and Chen.
For Tabules, according to dosage, medicine can account for 1 % by weight to 80 % by weight of formulation, more generally accounts for 5 % by weight to 60 % by weight of formulation.Except medicine, tablet is usually containing disintegrating agent.The example of disintegrating agent comprises sodium starch glycollate, Xylo-Mucine, calcium carboxymethylcellulose, cross-linked carboxymethyl cellulose sodium, Crospovidone, polyvinylpyrrolidone, methylcellulose gum, Microcrystalline Cellulose, low alkyl group replace hydroxypropylcellulose, starch, pregelatinized Starch and sodium alginate.Generally speaking, disintegrating agent can account for 1 % by weight to 25 % by weight of formulation, and such as 5 % by weight to 20 % by weight.
Tackiness agent is generally used for giving bond property to tablet formulation.The tackiness agent be applicable to comprises Microcrystalline Cellulose, gelatin, sugar, polyoxyethylene glycol, natural and synthetic gum, polyvinylpyrrolidone, pregelatinized Starch, hydroxypropylcellulose and Vltra tears.Tablet also can contain thinner, such as lactose (monohydrate, spray-dired monohydrate, anhydride etc.), N.F,USP MANNITOL, Xylitol, glucose, sucrose, Sorbitol Powder, Microcrystalline Cellulose, starch and calcium phosphate dibasic dihydrate.
Tablet also optionally comprises tensio-active agent (such as Sodium Lauryl Sulphate BP/USP and polysorbate80) and glidant (such as silicon-dioxide and talcum).When it is present, tensio-active agent can account for 0.2 % by weight to 5 % by weight of tablet, and glidant can account for 0.2 % by weight to 1 % by weight of tablet.
Tablet is usually also containing lubricant, the such as mixture of Magnesium Stearate, calcium stearate, Zinic stearas, sodium stearyl fumarate and Magnesium Stearate and Sodium Lauryl Sulphate BP/USP.Lubricant accounts for 0.25 % by weight to 10 % by weight of tablet usually, and such as 0.5 % by weight to 3 % by weight.
Other possible composition comprises antioxidant, tinting material, seasonings, sanitas and taste masked agent.
Exemplary tablet contain at the most about 80% medicine, about 10 % by weight to about 90 % by weight tackiness agent, the thinner of about 0 % by weight to about 85 % by weight, the disintegrating agent of about 2 % by weight to about 10 % by weight and about 0.25 % by weight to about 10 % by weight lubricant.
Tablet blends can directly or by Roller compaction to form tablet.Or, before tabletting, can by part wet granulation, non-slurry pelletizing or the melt pelletization of Tablet blends or adulterant, melting is coalescent or extrude.Final preparation can comprise one or more layer, and can by dressing or not by dressing; Even can be incapsulated.
The preparation of tablet, at the Pharmaceutical DosageForms:Tablets of H.Lieberman and L.Lachman, is discussed in the 1st volume (Marcel Dekker, New York, 1980).
People uses or the per os taken membrane agent for animals is generally pliable and tough water-soluble or water swellability thin-film dosage form, it is rapidly dissolvable or have mucoadhesive, and the compound of usual contained I, film-forming polymer, tackiness agent, solvent, wetting Agent for Printing Inks, softening agent, stablizer or emulsifying agent, viscosity modifier and solvent.Some components of preparation can play more than a kind of function.
The compound of formula I (or its pharmacy acceptable salt or its N-oxide compound) water soluble or water insoluble.Water-soluble cpds accounts for 1 % by weight to 80 % by weight of solute usually, and more generally 20 % by weight to 50 % by weight.The less ratio of composition can be accounted for compared with the compound of low-solubility, usually at the most solute 30 % by weight.Or the compound of formula I can be the form of many particles pearl.
Film-forming polymer can be selected from natural polysaccharide, protein or synthetic water colloid, and usually with 0.01 to 99 % by weight, more generally exists with 30 to 80 % by weight.
Other possible composition comprises antioxidant, tinting material, seasonings and odorant, sanitas, saliva stimulant, refrigerant, cosolvent (comprising oil), tenderizer, swelling agent, defoamer, tensio-active agent and taste masked agent.
Membrane agent of the present invention is usually by making the water-based thin film evaporation drying be coated on strippable back bracket or paper prepare.This can be undertaken in drying oven or drying alley (being generally combination coating moisture eliminator) or by lyophilize or vacuumize.
Solid preparation for oral administration can be formulated as release and/or modified release preparation immediately.Modified release preparation comprises delayed release, sustained release, pulse release, Co ntrolled release, Targeting delivery and program control delivery formulations.
The modified release preparation be applicable to for reaching object of the present invention is described in the 6th, 106, in No. 864 United States Patent (USP)s.The details of release tech (such as high energy dispersions and infiltration and the particle of dressing) that other is applicable to is found in the people such as Verma, and Pharmaceutical Technology On-line, in 25 (2), 1-14 (2001).Chewing ingot (chewing gum) is used to be described in WO 00/35298 to reach Co ntrolled release.
Compound of the present invention (comprising its pharmacy acceptable salt and N-oxide compound thereof) also can directly in blood flow, in muscle or to administration in internal organs.The means being applicable to administered parenterally comprise in intravenously, intra-arterial, intraperitoneal, sheath, in ventricle, in urethra, in breastbone, in encephalic, intramuscular, synovial membrane and subcutaneous administration.The device being applicable to administered parenterally comprises pin (comprising micropin) syringe, needleless injector and infusion techniques.
Parenteral administration is generally the aqueous solution, it can contain vehicle, such as salt, carbohydrate and buffer reagent (being such as buffered to pH is 3 to 9), but for some application, parenteral administration can be more suitable for being formulated as the sterile non-aqueous solution or dried forms that are combined with the vehicle (such as aseptic pyrogen-free water) be applicable to.
Aseptically such as preparing parenteral administration by freeze-drying can use standard pharmaceutical techniques well known to those skilled in the art easily to realize.
Solubleness for the preparation of the compound of the formula I of parenteral solution increases by using suitable preparation technique (such as mixing solubility enhancer).
Preparation for administered parenterally can be formulated as release and/or modified release preparation immediately.Modified release preparation comprises delayed release, sustained release, pulse release, Co ntrolled release, Targeting delivery and program control delivery formulations.Therefore, compound of the present invention can be formulated as suspensoid or solid, semisolid or thixotropic liquid, carrys out administration to provide the implanted storage tank form of the modified release of active compound.The example of such preparation comprises the support of coated with drug and comprises the semisolid gathering (DL-LACTIC ACID-oxyacetic acid (coglycolic acid) altogether) (PLGA) microballoon and the suspensoid of carrying medicament.
Compound of the present invention (comprising its pharmacy acceptable salt and N-oxide compound thereof) also can to skin or mucous membrane local, skin (interior) or percutaneous dosing.Exemplary formulations for this object comprises gelifying agent, hydrogel, lotion, solution, ointment, ointment, dusting powder (dusting powder), dressing, foaming agent, membrane agent, skin patch, bag medicine glutinous rice charta (wafer), implant, sponge, fiber, bandage and microemulsion.Also liposome can be used.Typical carriers comprises alcohol, water, mineral oil, whiteruss, white vaseline, glycerine, polyoxyethylene glycol and propylene glycol.Penetration enhancer can be mixed.See such as Finnin and Morgan, J.Pharm.Sci.1999,88,955-958.
Other means of topical comprise by electroporation, iontophoresis, phonophoresis, phonophoresis and micropin or needleless (such as Powderject tM, Bioject tMdeng) inject and send.
Preparation for topical can be formulated as release and/or modified release preparation immediately.Modified release preparation comprises delayed release, sustained release, pulse release, Co ntrolled release, Targeting delivery and program control delivery formulations.
Compound of the present invention (comprising its pharmacy acceptable salt and N-oxide compound thereof) also can in intranasal or by sucking administration, and it usually in the dry powder form from Diskus (separately; In form of mixtures, such as, with the dry adulterant of lactose; Or in blending ingredients particle form, such as mix with phosphatide (such as phosphatidylcholine)), in using or not using applicable propellent (such as 1,1,1,2-Tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoro-propane) under the aerosol spray form from pressurizing vessel, pump, atomizer (spray), spraying gun (such as use electrohydrodynamics to produce the spraying gun of fine mist) or atomizer (nebulizer), or be nose drop form.Use in nose, powder can comprise bioadhesive polymer, such as chitosan or cyclodextrin.
Solution containing compound of the present invention of pressurizing vessel, pump, atomizer (spray), spraying gun or atomizer (nebulizer) or suspension, described solution or suspension comprise such as ethanol, aqueous ethanolic solution or be applicable to disperse, solubilization activity material or extend active substance release other selective material, as the propellent of solvent and the optional tensio-active agent (such as Sorbitan Trioleate, oleic acid or lactic acid oligomer (oligolactic acid)) existed.
Before using in dry powder or suspension formulation, medicine turns to the size (being usually less than 5 microns) being adapted to pass through inhalation delivery through particulate.This realizes by any suitable breaking method, such as volution jet grinding, fluidised-bed spray grinding, the treatment with supercritical fluid forming nano particle, high pressure homogenization or spraying dry.
The powdered mixture containing compound of the present invention, applicable powdered substrate (such as lactose or starch) and usefulness conditioning agent (such as L-Leu, N.F,USP MANNITOL or Magnesium Stearate) can be formulated as the capsule (such as obtaining from gelatin or Vltra tears) of sucker or insufflator, blister pack agent and cartridge case.Lactose can be anhydrous or is monohydrate form.Other vehicle be applicable to comprises dextran, glucose, maltose, Sorbitol Powder, Xylitol, fructose, sucrose and trehalose.
Be applicable to use electrohydrodynamics can contain each compound of the present invention activating 1 μ g to 20mg to the pharmaceutical solutions producing the spraying gun of fine mist, and actuating volume can change at 1 μ L to 100 μ L.Exemplary formulations can the compound of contained I or its pharmacy acceptable salt, propylene glycol, sterilized water, ethanol and sodium-chlor.Other selective solvent that propylene glycol can be replaced to use comprises glycerine and polyoxyethylene glycol.
The seasonings (such as mentha camphor and l-Menthol) be applicable to or sweeting agent (such as asccharin or soluble saccharin) can be added into and be intended in those preparations of the present invention of suction/intranasal administration.
For sucking/preparation of intranasal administration can use such as PGLA to be formulated as release and/or modified release preparation immediately.Modified release preparation comprises delayed release, sustained release, pulse release, Co ntrolled release, Targeting delivery and program control delivery formulations.
When Diskus and aerosol, determine dose unit by sending quantitative valve.Unit of the present invention is configured to metered dose or " spray dose (puff) " that administration contains the compound of the formula I of 0.01-100mg usually.Total per daily dose can be 1 μ g to 200mg usually, and it can single dose form administration, or is more typically in all day with fractionated dose form administration.
Compound of the present invention can per rectum or intravaginal administration, such as, with suppository, hysterophore or enema forms administration.Theobroma oil is conventional suppository bases, but can use multiple surrogate time suitably.
Preparation for per rectum/vagina administration can be formulated as release and/or modified release preparation immediately.Modified release preparation comprises delayed release, sustained release, pulse release, Co ntrolled release, Targeting delivery and program control delivery formulations.
Compound of the present invention can, directly to eye or ear administration, be also the form of the drops of isotonic, that pH is in the Sterile Saline of adjustment micronized suspension or solution usually.Other preparation being suitable for eye and otic administration comprises ointment, gelifying agent, Biodegradable implants (such as Absorbable rod gel sponge, collagen) and not Biodegradable implants (such as silicone), bag medicine glutinous rice charta, eyeglass and granule or Vesicular system (such as vesicle (niosome) or liposome).Such as the polymkeric substance of cross linked polyacrylate, polyvinyl alcohol, hyaluronic acid, cellulose polymer compound (such as Vltra tears, Natvosol or methylcellulose gum) or assorted polysaccharide polymkeric substance (such as agarose gel) can be blended together with sanitas (such as benzalkonium chloride).Such preparation is also sent by iontophoresis.
Preparation for eye/otic administration can be formulated as release and/or modified release preparation immediately.Modified release preparation comprises delayed release, sustained release, pulse release, Co ntrolled release, Targeting delivery or program control delivery formulations.
Compound of the present invention can with soluble high-molecular entity (such as cyclodextrin and applicable derivative thereof, or the polymkeric substance containing polyoxyethylene glycol) combination, to improve solubleness, solubility rate, taste masked, bioavailability and/or stability when it uses in any aforementioned mode of administration.
Such as, find that Drug-cyclodextrin complexes can be used for most formulation and route of administration usually.Clathrate complex and non-clathrate complex can be used.As the replacement scheme with the direct complexing of medicine, cyclodextrin can be used as supplementary additive, is namely used as carrier, thinner or solubilizing agent.Be most commonly used to these objects for alpha-cylodextrin, beta-cyclodextrin and γ-cyclodextrin, the example is found in No. 91/11172, WO, No. WO94/02518 and WO No. 98/55148 international patent application.
Because one aspect of the present invention relates to treat disease/patient's condition described herein with the combination of the activeconstituents that can separate administration, combine pharmaceutical composition separately so the invention still further relates to kit form.Described medicine box comprises the salt of the compound of the two kinds of pharmaceutical composition separated: formula I, its prodrug or such compound or prodrug, and the second compound as described above.Medicine box comprises the means for the composition separated described in holding, such as container, the bottle separated or the foil packaging of separating.Described medicine box comprises the guidance of the component of separating for administration usually.When the component of separating such as with different dosage form (such as per os and parenteral) administration time, with different dosing interval administrations time, or prescriber need titration to combine independent component time, kit form is useful especially.
The example of such medicine box is so-called blister pack.Blister pack known by people, and is widely used in packaged pharmaceuticals unit dosage (tablet, capsule etc.) in packaging industry.Blister pack is made up of the thin slice of the relative rigidity material covered with transparent plastic material paillon foil usually.During wrapping process, in plastic foil, form groove.Described groove has size and the shape of tablet to be packaged or capsule.Then, tablet or capsule are put in a groove, and relative to plastic foil, the thin slice of a face seal relative rigidity material contrary with the direction forming groove in paillon foil front.Therefore, tablet or capsule are sealed in the groove between plastic foil and thin slice.In some embodiments, the intensity of described thin slice makes tablet or capsule can shift out from blister pack, and it by manually applying pressure on groove, thus forms opening in groove location in thin slice.Then, described tablet or capsule shift out by described opening.
Medicine box may need provide memory auxiliary, such as, be close to the numbering form of tablet or capsule, wherein numbering is corresponding to the number of days should taking in described tablet of specifying or capsule in scheme.Another example that such memory is assisted is the calendar of printing on card, such as following " first week, Monday, all second-class ... second week, Monday, Tuesday ... " etc.Other modification that memory is assisted can be apparent." per daily dose " can be the single tablet or capsule taken in the appointed day, or several pill or capsule.In addition, the per daily dose of the compound of formula I can be made up of a kind of tablet or capsule, and the per daily dose of the second compound can be made up of several tablet or capsule, and anti-going back so.Memory is auxiliary should reflect this situation.
In another specific embodiments of the present invention, provide through design with the divider of the order primary distribution per daily dose by desired use.Such as, described divider is equipped with memory auxiliary, to promote the conformability with scheme further.The example that such memory is assisted is the mechanical counter indicating the per daily dose number distributed.Another example that such memory is assisted is the battery powered micro-chip memory with liquid crystal readout or audio alert signal combination, and described liquid crystal readout or audio alert signal such as read date of taking a per daily dose and/or remind when take subsequent dose.
In more detail the present invention is described by specific embodiment.Following examples are provided for illustrative purposes, are not intended to limit the present invention by any way.Those skilled in the art can easily identify can through changing or revising the multiple nonessential parameter to produce substantially identical result.In following examples and preparation, " DMSO " means methyl-sulphoxide, when mentioning concentration, " N " means equivalent concentration when referring to concentration, and " M " means mole, and " mL " means milliliter, " mmol " means mmole, " μm ol " means micromole, and " eq. " means equivalent, and " DEG C " means degree Celsius, " MHz " means megahertz, and " HPLC " means high performance liquid chromatography.
Embodiment
Experiment is carried out usually under inert atmosphere (nitrogen or argon gas), when particularly adopting wherein the reagent of oxygen or moisture-sensitive or intermediate.Being purchased solvent and namely reagent use without being further purified usually, comprising anhydrous solvent time suitable and (being generally from Aldrich Chemical Company, the Sure-Seal of Milwaukee, Wisconsin tMproduct).Product is proceeding further reaction or is submitting to for usually dry under vacuo before carrying out bioassay.Mass-spectrometric data detects report by C/MS (liquid chromatography-mass spectrography) (LCMS), atmospheric pressure chemical ionization (APCI) or vapor-phase chromatography-mass spectroscopy (GCMS).The chemical shift of nucleus magnetic resonance (NMR) data represents with parts per million (ppm) (ppm, δ) with reference to the remaining peak from adopted deuterated solvents.In certain embodiments, carry out chiral separation to be separated the atropisomer (or resistance turns enantiomer) of some compound of the present invention (in certain embodiments, according to its eluotropic series, be separated atropisomer is appointed as ENT-1 and ENT-2).In certain embodiments, polariscope is used to measure the specific rotation of atropisomer.According to its spin data observed (or its concrete spin data), the atropisomer (or resistance turns enantiomer) with dextrorotation opticity is appointed as (+)-atropisomer [or (+) resistance turns enantiomer], has the atropisomer (or resistance turns enantiomer) revolving opticity counterclockwise and is appointed as (-)-atropisomer [or (-) resistance turns enantiomer].
To the synthesis with reference to the method in other embodiment or method, reaction conditions (reaction times length and temperature) alterable.Generally speaking, carry out tlc or mass spectroscopy after reacting, and carry out aftertreatment time suitably.Between experiment, purifying alterable: generally speaking, selects to be used for the solvent of elutriant/gradient and solvent ratio to provide suitable R for retention time.
Preparation
Preparation P1-P8 describes for the preparation of some raw materials of some compound of the present invention or the preparation of intermediate.
Preparation P1
The chloro-1-{ of 4-[2-(TMS) oxyethyl group] methyl }-1H-pyrrolo-[3,2-c] pyridine (P1)
Chloro-for 4-1H-pyrrolo-[3,2-c] pyridine (98%, 2.0g, 13mmol) and the mixture of tetrahydrofuran (THF) (20mL) are cooled to 0 DEG C.Through 5 minutes portion-wise addition sodium hydrides (in oil 60%, 1.03g, 25.8mmol), and at 0 DEG C stirred reaction mixture 10 minutes.With after dropwise added 2-(TMS) ethoxyl methyl chlorine (3.40mL, 19.3mmol) through 5 minutes, and at 0 DEG C, continue stirring 15 minutes.With saturated aqueous ammonium chloride cancellation reaction mixture; Be extracted with ethyl acetate water layer twice, and with the organic layer that dried over sodium sulfate merges, filter, and concentrate in a vacuum.Silica gel chromatography (gradient: 10% to 20% ethyl acetate in heptane), obtains the product in colorless oil.Yield: 2.64g, 9.33mmol, 72%.LCMS m/z 283.0[M+H +]。 1H NMR(400MHz,CDCl 3)δ8.13(d,J＝5.8Hz,1H),7.34(dd,J＝5.8,0.7Hz,1H),7.25(d,J＝3.3Hz,1H),6.69(dd,J＝3.3,0.7Hz,1H),5.48(s,2H),3.46(dd,J＝8.2,8.1Hz,2H),0.89(dd,J＝8.2,8.1Hz,2H),-0.05(s,9H)。
Preparation P2
4-chloro-1H-pyrrolo-[3,2-c] pyridine-1-t-butyl formate (P2)
To the chloro-1H-pyrrolo-[3 of 4-, 2-c] pyridine (300mg, 1.97mmol) and 4-(dimethylamino) pyridine (97%, 124mg, tert-Butyl dicarbonate (99% is added in solution 0.984mmol) in acetonitrile (3mL), 650mg, 2.95mmol), and at room temperature stirred reaction mixture 18 hours.Remove volatile matter in a vacuum, and carry out Purification by silica gel chromatography (gradient: 0% to 50% ethyl acetate in heptane), obtain the product in white solid.Yield: 410mg, 1.62mmol, 82%.LCMSm/z 253.0[M+H +]。 1H NMR(400MHz,CDCl 3)δ8.24(d,J＝5.7Hz,1H),7.95(br d,J＝5.7Hz,1H),7.65(d,J＝3.7Hz,1H),6.72(dd,J＝3.7,0.8Hz,1H),1.70(s,9H)。
Preparation P3
The chloro-1-of 4-(tetrahydrochysene-2H-pyrans-2-base)-1H-pyrazolo [4,3-c] pyridine (P3)
To the chloro-1H-pyrazolo [4 of 4-, 3-c] pyridine (20.0g, in suspension 130mmol) in methylene dichloride (400mL), order adds tosic acid monohydrate (2.4g, 13mmol) and 3,4-dihydro-2H-pyrans (99%, 45mL, 520mmol).Reaction mixture is at room temperature stirred 24 hours, now washs with saturated sodium bicarbonate aqueous solution.Use dried over sodium sulfate organic layer, filter, and concentrate in a vacuum.Carry out purifying by silica gel chromatography (elutriant: 10% in heptane, subsequently 30%, subsequently 50% ethyl acetate), obtain the product in white solid.Yield: 27.51g, 115.7mmol, 89%.LCMSm/z 238.1[M+H +]。 1H NMR(400MHz,CDCl 3)δ8.19(d,J＝6.0Hz,1H),8.16(d,J＝0.9Hz,1H),7.47(dd,J＝6.0,0.9Hz,1H),5.73(br dd,J＝9.0,2.7Hz,1H),3.97-4.04(m,1H),3.72-3.80(m,1H),2.43-2.53(m,1H),2.07-2.20(m,2H),1.65-1.85(m,3H)。
Preparation P4
The chloro-6-methyl isophthalic acid of 4--(tetrahydrochysene-2H-pyrans-2-base)-1H-pyrazolo [4,3-c] pyridine (P4)
The synthesis of step 1.4-chloro-6-methyl isophthalic acid H-pyrazolo [4,3-c] pyridine (C1)
To 2, hydrazine monohydrate (9.52g is added in the solution of 4-bis-chloro-6-picoline-3-formaldehyde (12g, 63mmol) in 1,2-ethylene dichloride (200mL), 0.190mol), reacting by heating mixture 18 hours and at 80 DEG C.After removing solvent in a vacuum, residue to be suspended in water (150mL) and to stir 30 minutes.Collect gained precipitation by filtering, and with sherwood oil (2 × 250mL) washing, be suspended in chloroform (150mL) subsequently, stir 30 minutes and filter.Repeat chloroform and suspend twice, obtain the product in white solid.Yield: 6.7g, 40mmol, 63%.LCMS m/z 168.1[M+H +]。 1H NMR(400MHz,DMSO-d 6)δ13.70(br s,1H),8.21(s,1H),7.38(s,1H),2.52(s,3H)。
The synthesis of step 2.P4
To C1 (250mg, 1.49mmol) and in the suspension of molecular sieve in methylene dichloride (10mL), order adds tosic acid monohydrate (29mg, 0.15mmol) and 3,4-dihydro-2H-pyrans (99%, 205 μ L, 2.39mmol).Reaction mixture is at room temperature stirred 4 hours, now filters, concentrate in a vacuum, and by heptane wash three times.Carry out purifying by silica gel chromatography (gradient: 20% to 50% ethyl acetate in heptane), obtain the product in colorless oil.Yield: 65mg, 0.26mmol, 17%.LCMS m/z 252.1[M+H +]。 1h NMR (400MHz, CDCl 3), characteristic peak: δ 8.08 (d, J=0.9Hz, 1H), 7.26-7.27 (m, 1H), 5.67 (dd, J=9.1,2.8Hz, 1H), 3.99-4.05 (m, 1H), 3.71-3.79 (m, 1H), 2.65 (d, J=0.8Hz, 3H), 2.06-2.2 (m, 2H).
Preparation P5
The chloro-7-methoxyl group of 4--1-(tetrahydrochysene-2H-pyrans-2-base)-1H-pyrazolo [4,3-c] pyridine (P5)
The synthesis of step 1.2-chloro-5-methoxyl-3-picoline 1-oxide compound (C2)
3-chloroperoxybenzoic acid (70%, 695mg, 2.82mmol) is added in the solution of 2-chloro-5-methoxyl-3-picoline (370mg, 2.35mmol) in methylene dichloride (10mL).After at room temperature stirring 18 hours, concentrated reaction mixture in a vacuum, and carry out purifying by silica gel chromatography (gradient: 0% to 10% methyl alcohol in ethyl acetate), obtain the product in white solid.Yield: 370mg, 2.13mmol, 91%. 1H NMR(400MHz,CD 3OD)δ8.14(d,J＝2.5Hz,1H),7.23(d,J＝2.3Hz,1H),3.88(s,3H),2.44(s,3H)。
The synthesis of step 2.2-chloro-5-methoxyl-3-methyl-4-nitropyridine 1-oxide compound (C3)
Concentrated nitric acid (2.5mL) is dropwise added in 0 DEG C of solution of C2 (350mg, 2.02mmol) in the vitriol oil (2.5mL).At 90 DEG C, reacting by heating mixture 1 hour, is cooled to room temperature subsequently and is poured on trash ice.With saturated aqueous sodium carbonate, gained mixture is neutralized to pH 6-7, and is extracted with ethyl acetate.Wash the organic layer of merging with water, with saturated sodium-chloride water solution washing, through dried over mgso, filter, and concentrate in a vacuum, obtain the product in faint yellow solid shape.Yield: 370mg, 1.69mmol, 84%.LCMS m/z 219.0,221.1[M+H +]。 1H NMR(400MHz,DMSO-d 6)δ8.65(s,1H),3.94(s,3H),2.31(s,3H)。
The synthesis of step 3.2-chloro-5-methoxyl-3-picoline-4-amine (C4)
In the solution of C3 (350mg, 1.60mmol) in acetic acid (8mL), add iron powder (700mg, 12mmol), and at 100 DEG C reacting by heating mixture 1 hour, be cooled to room temperature subsequently.After by diatomite filtration and by ethyl acetate and the thorough washed filter bed of methyl alcohol, the concentrated filtrate merged in a vacuum.Dilute residue with saturated sodium bicarbonate aqueous solution, and be extracted with ethyl acetate.Wash the organic layer of merging with water, with saturated sodium-chloride water solution washing, through dried over mgso, filter, and under reduced pressure concentrate.Silica gel chromatography (gradient: 50% to 75% ethyl acetate in heptane), obtains the product in white solid.Yield: 240mg, 1.39mmol, 87%.LCMS m/z 173.0[M+H +]。 1H NMR(400MHz,CDCl 3)δ7.65(s,1H),4.38(br s,2H),3.91(s,3H),2.20(s,3H)。
The synthesis of the chloro-7-methoxyl group of step 4.4--1H-pyrazolo [4,3-c] pyridine (C5)
To C4 (200mg, Sodium Nitrite (98% is added in solution 1.16mmol) in acetic acid (8mL), 326mg, 4.63mmol) solution in water (0.6mL), and at 75 DEG C reacting by heating mixture 1 hour.After reaction mixture is cooled to room temperature, concentrate in a vacuum, with saturated sodium bicarbonate aqueous solution dilution, and be extracted with ethyl acetate.With the organic layer that saturated sodium-chloride water solution washing merges, through dried over mgso, filtration, and under reduced pressure concentrate.Silica gel chromatography (gradient: 25% to 50% ethyl acetate in heptane), obtains the product in yellow solid.Yield: 140mg, 0.763mmol, 66%.LCMS m/z 184.0[M+H +]。 1H NMR(400MHz,CDCl 3)δ8.17(s,1H),7.74(s,1H),4.06(s,3H)。
The synthesis of step 5.P5
C5 is converted into product by described method when synthesizing the chloro-1-of 4-(tetrahydrochysene-2H-pyrans-2-base)-1H-pyrazolo [4,3-c] pyridine P3 that is used in preparation P3.Obtain the product in faint yellow oily, it is solidified on standing.Yield: 120mg, 0.448mmol, 41%.LCMS m/z 268.1[M+H +]。 1HNMR(400MHz,CDCl 3)δ8.11-8.12(m,1H),7.72(s,1H),6.12(dd,J＝10.0,2.6Hz,1H),4.06(s,3H),4.04-4.10(m,1H),3.69-3.77(m,1H),2.51-2.62(m,1H),2.12-2.21(m,1H),2.00-2.08(m,1H),1.5-1.8(m,3H)。
Preparation P6
The chloro-1-{ of 4-[2-(TMS) oxyethyl group] methyl }-1H-pyrazolo [4,3-c] pyridine (P6)
Use is prepared in P1 method described when synthesizing P1 and chloro-for 4-1H-pyrazolo [4,3-c] pyridine is converted into product.Be separated the product in white solid.Yield: 686mg, 2.42mmol, 50%. 1H NMR(400MHz,CDCl 3)δ8.24(d,J＝5.8Hz,1H),8.17(s,1H),7.43(d,J＝5.8Hz,1H),5.74(s,2H),3.54-3.60(m,2H),0.86-0.92(m,2H),-0.05(s,9H)。
Preparation P7
The chloro-1-{ of 4-[2-(TMS) oxyethyl group] methyl }-1H-pyrrolo-[3,2-c] pyridine-3-formonitrile HCN (P7)
The synthesis of the chloro-3-of step 1.4-iodo-1H-pyrrolo-[3,2-c] pyridine (C6)
N-iodine succimide (1.3g, 5.8mmol) is added in 0 DEG C of solution of the chloro-1H-pyrrolo-[3,2-c] pyridine (0.60g, 3.9mmol) of 4-in DMF (10mL).At room temperature stirred reaction mixture 18 hours, then concentrates in a vacuum.Carry out purifying by silica gel chromatography (0% to 50% ethyl acetate in sherwood oil), obtain the product in yellow solid.Yield: 900mg, 3.2mmol, 82%. 1H NMR(400MHz,CDCl 3)δ8.10(d,J＝5.5Hz,1H),7.42(d,J＝2.5Hz,1H),7.34(d,J＝5.8Hz,1H)。
The iodo-1-{ of the chloro-3-of step 2.4-[2-(TMS) oxyethyl group] methyl } synthesis of-1H-pyrrolo-[3,2-c] pyridine (C7)
Sodium hydride (in mineral oil 60%, 168mg, 4.2mmol) is added in 0 DEG C of solution of C6 (900mg, 3.2mmol) in DMF (3mL) and tetrahydrofuran (THF) (70mL).After five minutes, in cold mixt, 2-(TMS) ethoxyl methyl chlorine (592mg, 3.55mmol) is added.At room temperature stirred reaction mixture 3 hours, is cooled to 0 DEG C subsequently, and processes with extra sodium hydride (56mg, 1.4mmol) and 2-(TMS) ethoxyl methyl chlorine (197mg, 1.18mmol).After at room temperature stirring 18 hours, with saturated sodium-chloride water solution (100mL) diluted reaction mixture, and extract by ethyl acetate (2 × 100mL).The dry organic layer merged, filters, and concentrates in a vacuum.Silica gel chromatography (gradient: 0% to 30% ethyl acetate in sherwood oil), obtains the product in yellow oily.Yield: 650mg, 1.59mmol, 50%. 1H NMR(400MHz,CDCl 3)δ8.14(d,J＝6.0Hz,1H),7.39(d,J＝6.0Hz,1H),7.38(s,1H),5.44(s,2H),3.44-3.50(m,2H),0.86-0.92(m,2H),-0.03(s,9H)。
The synthesis of step 3.P7
To C7 (1.2g, 2.9mmol) and cupric cyanide (I) (540mg, 6.0mmol) in 1, interpolation three (dibenzalacetone) two palladium (0) (275mg in mixture in 4-dioxane (40mL), 0.300mmol) and two (phenylbenzene the phosphine) (BINAP of 1,1'-naphthyl naphthalene-2,2'-bis-base, 540mg, 0.87mmol).At 110 DEG C after stirred reaction mixture 18 hours, filter and under reduced pressure concentrate.Carry out purifying by silica gel chromatography (gradient: 5% to 20% ethyl acetate in sherwood oil), obtain the product in yellow solid.Yield: 380mg, 1.2mmol, 41%. 1H NMR(400MHz,CDCl 3)δ8.27(d,J＝5.8Hz,1H),7.80(s,1H),7.43(d,J＝5.8Hz,1H),5.52(s,2H),3.47-3.54(m,2H),0.88-0.95(m,2H),-0.02(s,9H)。
Preparation P8
6-(4-hydroxy-2-methyl phenyl)-1,5-dimethylpyrazine-2 (1H)-one (P8)
The synthesis of step 1.1-(4-methoxyl group-2-aminomethyl phenyl) the third-2-ketone (C8)
Carry out four batches of these experiments (4 × 250g substrate).At 100 DEG C, by tributyl (methoxyl group) stannane (400g, 1.24mol), the bromo-4-methoxyl group of 1--2-methylbenzene (250g, 1.24mol), acetic acid third-1-alkene-2-base ester (187g, 1.87mol), acid chloride (II) (7.5g, 33mmol) and three (2-aminomethyl phenyl) phosphine (10g, 33mmol) in toluene (2L), stir 18 hours together.After cooling to room-temperature, by potassium fluoride aqueous solution (4M, 400mL) reaction mixture, and stir 2 hours at 40 DEG C.Dilute gained mixture with toluene (500mL), and pass through diatomite filtration; With the abundant washed filter bed of ethyl acetate (2 × 1.5L).Through the organic phase of dried over sodium sulfate from the filtrate merged, filter, and concentrate in a vacuum.Carry out purifying by silica gel chromatography (gradient: 0% to 5% ethyl acetate in sherwood oil), obtain the product in yellow oily.The yield merged: 602g, 3.38mol, 68%.LCMS m/z 179.0[M+H +]。 1H NMR(400MHz,CDCl 3)δ7.05(d,J＝8.3Hz,1H),6.70-6.77(m,2H),3.79(s,3H),3.65(s,2H),2.22(s,3H),2.14(s,3H)。
The synthesis of step 2.1-(4-methoxyl group-2-aminomethyl phenyl) propane-1,2-diketone (C9)
C8 (6.00g, 33.7mmol) and tin anhydride (7.47g, 67.3mmol) are suspended in Isosorbide-5-Nitrae-dioxane (50mL), and heat 18 hours at 100 DEG C.Reaction mixture is cooled to room temperature, and passes through diatomite filtration; Concentrated filtrate in a vacuum.Silica gel chromatography (elutriant: 10% ethyl acetate in heptane), obtains the product in aureus oily.Yield: 2.55g, 13.3mmol, 39%.LCMS m/z 193.1[M+H +]。 1h NMR (400MHz, CDCl 3) δ 7.66 (d, J=8.6Hz, 1H), 6.81 (half of br d, AB quartet, J=2.5Hz, 1H), the 6.78 (half of br dd, ABX pattern, J=8.7,2.6Hz, 1H), 3.87 (s, 3H), 2.60 (br s, 3H), 2.51 (s, 3H).
The synthesis of step 3.6-(4-methoxyl group-2-aminomethyl phenyl)-5-methylpyrazine-2 (1H)-one (C10)
C9 (4.0g, 21mmol) and acetic acid G-NH2 (2.79g, 20.8mmol) are dissolved in methyl alcohol (40mL), and are cooled to-10 DEG C.Add aqueous sodium hydroxide solution (12N, 3.5mL, 42mmol), and gained mixture is slowly warming up to room temperature.After stirring 3 days, concentrated reaction mixture in a vacuum.Dilute with water residue, and add 1N aqueous hydrochloric acid until pH is about 7.Be extracted with ethyl acetate aqueous phase, and with the organic extract that saturated sodium-chloride water solution washing merges, through dried over mgso, filter, and under reduced pressure concentrate.Residue obtained 3:1 ethyl acetate/heptane is made slurry, stirs 5 minutes, filter, and concentrate in a vacuum.Silica gel chromatography (elutriant: ethyl acetate), obtain the product in brown solid, this product contains 15% non-required regional isomer; Namely this material uses without being further purified.Yield: 2.0g.LCMS m/z 231.1[M+H +]。 1H NMR(400MHz,CDCl 3)δ8.09(s,1H),7.14(d,J＝8.2Hz,1H),6.82-6.87(m,2H),3.86(s,3H),2.20(s,3H),2.11(s,3H)。
The synthesis of step 4.6-(4-methoxyl group-2-aminomethyl phenyl)-1,5-dimethylpyrazine-2 (1H)-one (C11)
C10 (from abovementioned steps, 1.9g) is dissolved in DMF (40mL).Add lithiumbromide (0.86g, 9.9mmol) and two (TMS) ammonification sodium (95%, 1.91g, 9.89mmol), and stir gained solution 30 minutes.Add methyl iodide (0.635mL, 10.2mmol), and at room temperature continue stirring 18 hours.Dilute with water reaction mixture subsequently, and make pH value reach about 7 by slow portion-wise addition 1N aqueous hydrochloric acid.Be extracted with ethyl acetate water layer, and wash the organic layer several of merging with water, through dried over mgso, filter, and concentrated.Silica gel chromatography (gradient: 75% to 100% ethyl acetate in heptane), obtains the product in viscous orange oily.Yield after two steps: 1.67g, 6.84mmol, 33%.LCMS m/z 245.1[M+H +]。 1H NMR(400MHz,CDCl 3)δ8.17(s,1H),7.03(br d,J＝8Hz,1H),6.85-6.90(m,2H),3.86(s,3H),3.18(s,3H),2.08(br s,3H),2.00(s,3H)。
The synthesis of step 5.P8
The solution of boron tribromide in methylene dichloride (1M, 22mL, 22mmol) is added in-78 DEG C of solution of C11 (1.8g, 7.37mmol) in methylene dichloride (40mL).Remove cooling bath after 30 minutes, and make reaction mixture be warming up to room temperature and stir 18 hours.Reactant is cooled to-78 DEG C, and slowly adds methyl alcohol (10mL); Gained mixture is slowly warming up to room temperature.Concentrated reaction mixture in a vacuum, adds methyl alcohol (20mL), and under reduced pressure enriched mixture again.Dilute residue with ethyl acetate (300mL) and water (200mL), and make water layer reach pH 7 by portion-wise addition saturated aqueous sodium carbonate.Mixture is extracted by ethyl acetate (3 × 200mL).With the organic extract that water and saturated sodium-chloride water solution washing merge, through dried over mgso, filter, and concentrate in a vacuum, obtain the product in hazel-color solid shape.Yield: 1.4g, 6.0mmol, 81%.LCMS m/z 231.1[M+H +]。 1H NMR(400MHz,CDCl 3)δ8.21(s,1H),6.98(d,J＝8.2Hz,1H),6.87-6.89(m,1H),6.85(br dd,J＝8.2,2.5Hz,1H),3.22(s,3H),2.06(br s,3H),2.03(s,3H)。
Embodiment 1
4-[4-(4,6-dimethyl pyrimidine-5-base)-3-fluorophenoxy]-1H-pyrrolo-[3,2-c] pyridine (1)
Step 1.4-(the bromo-3-fluorophenoxy of 4-)-1-{ [2-(TMS) oxyethyl group] methyl } synthesis of-1H-pyrrolo-[3,2-c] pyridine (C12)
By P1 (2.9g, 10mmol), the bromo-3-fluorophenol of 4-(3.4g, 18mmol), acid chloride (II) (168mg, 0.748mmol), 4,5-two (diphenylphosphino)-9,9-dimethyl ton (Xantphos, 0.87g, 1.5mmol) and the mixture of cesium carbonate (9.8g, 30mmol) in Isosorbide-5-Nitrae-dioxane (60mL) stir 4 hours at 120 DEG C.Filtering mixt, in a vacuum concentrated filtrate, and carry out Purification by silica gel chromatography (elutriant: 10:1 petrol ether/ethyl acetate), obtain the product in colorless oil.Yield: 1.6g, 3.7mmol, 37%. 1H NMR(400MHz,CDCl 3)δ7.90(d,J＝5.8Hz,1H),7.55(dd,J＝8.5,8.0Hz,1H),7.17-7.21(m,2H),7.08(dd,J＝9.4,2.6Hz,1H),6.94-6.99(m,1H),6.68(d,J＝3.3Hz,1H),5.49(s,2H),3.50(t,J＝8.0Hz,2H),0.91(t,J＝8.1Hz,2H),-0.04(s,9H)。
Step 2.4-[the fluoro-4-of 3-(4,4,5,5-tetramethyl--1,3,2-dioxa boron penta ring-2-base) phenoxy group]-1-{ [2-(TMS) oxyethyl group] methyl } synthesis of-1H-pyrrolo-[3,2-c] pyridine (C13)
By C12 (1.2g, 2.7mmol), 4,4,4', 4', 5,5,5', 5'-prestox-2, two-1,3, the 2-dioxa boron penta ring (1.38g of 2'-, 5.43mmol), potassium acetate (0.8g, 8mmol) and [two (diphenylphosphino) ferrocene of 1,1'-] palladium chloride (II) (150mg, mixture 0.20mmol) in Isosorbide-5-Nitrae-dioxane (20mL) stirs 5 hours at 120 DEG C.After the reaction was completed, filtering mixt, and under reduced pressure concentrated filtrate.Use silica gel chromatography (elutriant: 15:1 petrol ether/ethyl acetate) to carry out purifying, obtain the product in orange oily.Yield: 0.94g, 1.9mmol, 70%. 1H NMR(400MHz,CDCl 3)δ7.92(d,J＝5.8Hz,1H),7.77(dd,J＝7.9,7.2Hz,1H),7.19(d,J＝5.9Hz,1H),7.17(d,J＝3.3Hz,1H),6.99-7.03(m,1H),6.90-6.94(m,1H),6.62(d,J＝3.3Hz,1H),5.49(s,2H),3.49(t,J＝8.1Hz,2H),1.36(s,12H),0.90(t,J＝8.2Hz,2H),-0.04(s,9H)。
Step 3.4-[4-(4,6-dimethyl pyrimidine-5-base)-3-fluorophenoxy]-1-{ [2-(TMS) oxyethyl group] methyl } synthesis of-1H-pyrrolo-[3,2-c] pyridine (C14)
By C13 (427mg, 0.881mmol), 5-bromo-4,6-dimethyl pyrimidine (150mg, 0.802mmol), three (dibenzalacetone) two palladium (0) (147mg, 0.160mmol), tricyclohexyl phosphine (90mg, 0.32mmol) and potassiumphosphate (341mg, 1.61mmol) in heating 2 hours at 120 DEG C under microwave irradiation containing the mixture in the 5 Isosorbide-5-Nitrae-dioxanes (4mL) dripped.Filtering mixt, under reduced pressure concentrated filtrate, and carry out Purification by preparative silica gel thin-layer chromatography (elutriant: ethyl acetate), obtain product, namely this product uses without being further purified.Yield: 180mg, 0.387mmol, 48%.LCMS m/z 465.3[M+H +]。
The synthesis of step 4.4-[4-(4,6-dimethyl pyrimidine-5-base)-3-fluorophenoxy]-1H-pyrrolo-[3,2-c] pyridine (1)
The solution of C14 (180mg, 0.387mmol) in trifluoroacetic acid (6mL) is heated to 90 DEG C, continues 2 hours.Under reduced pressure enriched mixture, and residue is dissolved in acetonitrile (5mL) and water (1mL).Add solid carbonic acid potassium (1g), and mixture is refluxed 2 hours.Filtering suspension liquid, and concentrated filtrate in a vacuum.By preparing high-efficient liquid chromatography of oppisite phase (post: Phenomenex Synergi C18,4 μm; Mobile phase A: 0.1% formic acid in water; Mobile phase B: 0.1% formic acid in acetonitrile; Gradient: 18% to 28%B) carry out purifying, obtain the product in white solid.Yield: 114mg, 0.341mmol, 88%.LCMS m/z 334.9[M+H +]。 1H NMR(400MHz,CD 3OD)δ8.96(s,1H),8.01(d,J＝6.5Hz,1H),7.67(d,J＝6.5Hz,1H),7.61(d,J＝3.0Hz,1H),7.47-7.58(m,2H),7.41(br d,J＝8.5Hz,1H),6.17(d,J＝3.0Hz,1H),2.39(s,6H)。
Embodiment 2
4-[4-(Isosorbide-5-Nitrae-dimethyl-1H-pyrazoles-5-base)-3-methylphenoxy]-1H-pyrrolo-[3,2-c] pyridine (2)
Step 1.4-(the bromo-3-methylphenoxy of 4-)-1-{ [2-(TMS) oxyethyl group] methyl } synthesis of-1H-pyrrolo-[3,2-c] pyridine (C15)
By P1 (326mg in sealable pipe, 1.15mmol), the bromo-3-methylphenol of 4-(216mg, 1.15mmol), di-t-butyl [3,4,5,6-tetramethyl--2', 4', 6'-tri-(the third-2-base) biphenyl-2-base] phosphine (97%, 114mg, 0.230mmol), acid chloride (II) (95%, 19.1mg, 80.8 μm of ol) and cesium carbonate (1.13g, 3.47mmol) in 1, merge in 4-dioxane (7mL), and at 130 DEG C reacting by heating mixture 18 hours.Add ethyl acetate, and by diatomite filtration mixture, concentrate in a vacuum and pass through silica gel chromatography (gradient: 0% to 50% ethyl acetate in heptane) purifying twice.Obtain the product in oily, it is still containing some starting phenol.Yield: 395mg, <0.91mmol, <79%.LCMS m/z 434.9[M+H +]。 1h NMR (500MHz, CDCl 3), only product peak: δ 7.91 (d, J=5.9Hz, 1H), 7.52 (d, J=8.5Hz, 1H), 7.19-7.22 (m, 2H), 7.12 (br d, J=2.7Hz, 1H), 6.94 (br dd, J=8.7,2.8Hz, 1H), 6.69 (br d, J=3.2Hz, 1H), 5.51 (s, 2H), 3.51-3.56 (m, 2H), 2.36 (s, 3H), 0.92-0.97 (m, 2H), 0.01 (s, 9H).
Step 2.4-[4-(Isosorbide-5-Nitrae-dimethyl-1H-pyrazoles-5-base)-3-methylphenoxy]-1-{ [2-(TMS) oxyethyl group] methyl } synthesis of-1H-pyrrolo-[3,2-c] pyridine (C16)
At room temperature to C15 (100mg, 0.231mmol), 1,1 is added in 4-dioxane (2mL) and the mixture of water (0.5mL), 4-dimethyl-5-(4,4,5,5-tetramethyl--1,3,2-dioxa boron penta ring-2-base)-1H-pyrazoles (56mg, 0.25mmol), [1,1'-two (diphenylphosphino) ferrocene] palladium chloride (II) (25.6mg, 0.0350mmol) and salt of wormwood (97mg, 0.70mmol).Stirred reaction mixture 1 hour at 120 DEG C; After cooling to room-temperature, filtering mixt and concentrated filtrate in a vacuum.Purifying is carried out, the product of the oily that obtains taking on a red color by preparative silica gel thin-layer chromatography (elutriant: 1:1 petrol ether/ethyl acetate).Yield: 51mg, 0.11mmol, 48%. 1H NMR(400MHz,CD 3OD)δ7.80(d,J＝6.0Hz,1H),7.43(d,J＝3.3Hz,1H),7.37-7.40(m,2H),7.21(d,J＝8.3Hz,1H),7.16(br d,J＝2.0Hz,1H),7.08(br dd,J＝8.3,2.5Hz,1H),6.61(d,J＝3.3Hz,1H),5.60(s,2H),3.61(s,3H),3.51-3.57(m,2H),2.09(s,3H),1.91(s,3H),0.85-0.91(m,2H),-0.06(s,9H)。
The synthesis of step 3.4-[4-(Isosorbide-5-Nitrae-dimethyl-1H-pyrazoles-5-base)-3-methylphenoxy]-1H-pyrrolo-[3,2-c] pyridine (2)
The solution of C16 (51mg, 0.11mmol) in trifluoroacetic acid (2mL) is stirred 1 hour at 80 DEG C.After cooling to room-temperature, enriched mixture in a vacuum, obtain { 4-[4-(1,4-dimethyl-1H-pyrazoles-5-base)-3-methylphenoxy]-1H-pyrrolo-[3,2-c] pyridine-1-base } methyl alcohol (C17) (38mg, 100%), itself and salt of wormwood (100mg), acetonitrile (2mL) and water (0.3mL) are merged.This reaction mixture is stirred 24 hours at 80 DEG C-85 DEG C.Reaction mixture is cooled to room temperature, and under reduced pressure concentrates; Carry out purifying by preparative silica gel thin-layer chromatography (elutriant: 1:3 petrol ether/ethyl acetate), obtain the product in white solid.Yield: 16mg, 50 μm of ol, 45%.LCMS m/z 318.9[M+H +]。 1H NMR(400MHz,CD 3OD)δ7.71(d,J＝5.5Hz,1H),7.38(s,1H),7.32(d,J＝3.5Hz,1H),7.23(d,J＝6.0Hz,1H),7.20(d,J＝8.5Hz,1H),7.14(d,J＝2.5Hz,1H),7.06(dd,J＝8.3,2.3Hz,1H),6.53(d,J＝3.0Hz,1H),3.60(s,3H),2.09(s,3H),1.91(s,3H)。
Embodiment 3 and 4
(+)-4,6-dimethyl-5-[2-methyl-4-(1H-pyrazolo [4,3-c] pyridin-4-yl oxygen base) phenyl] pyridazine-3 (2H)-one (3) and (-)-4,6-dimethyl-5-[2-methyl-4-(1H-pyrazolo [4,3-c] pyridin-4-yl oxygen base) phenyl] pyridazine-3 (2H)-one (4)
The synthesis of step 1.4-hydroxyl-3,5-dimethyl furan-2 (5H)-one (C18)
According to people such as D.Kalaitzakis, the method for Tetrahedron:Asymmetry 2007,18,2418-2426 makes 3-oxopentanoic acid methyl ester methylate, and obtains 2-methyl-3-oxopentanoic acid methyl ester; Use 1 equivalent bromine process in chloroform subsequently, obtain the bromo-2-methyl of 4--3-oxopentanoic acid methyl ester.This thick material (139g, 586mmol) is slowly added in 0 DEG C of solution of potassium hydroxide (98.7g, 1.76mol) in water (700mL).During adding, internal reaction temperature rises to 30 DEG C.By reaction mixture vigorous stirring 4 hours in ice bath, now make its acidifying by slowly adding concentrated hydrochloric acid.After being extracted with ethyl acetate, make water layer saturated with solid sodium chloride, and extract three times again by ethyl acetate.With the organic layer that saturated sodium-chloride water solution washing merges, through dried over mgso, filter, and under reduced pressure concentrate, obtain the mixture (81.3g) of oil and solid.This material is suspended in chloroform (200mL); Remove solid by filtering, and wash with chloroform (2 × 50mL).The concentrated filtrate merged in a vacuum, and process with the mixture (300mL) of heptane and ether 3:1.By violent for mixture vortex, until some oil start solidification.Under reduced pressure concentrate subsequently, obtain oily solid (60.2g).Adding the mixture (300mL) of heptane and ether 3:1 and after vigorous stirring 10 minutes, collect solid by filtering, obtaining is the product of pale solid shape.Yield: 28.0g, 219mmol, 37%. 1H NMR(400MHz,CDCl 3)δ4.84(br q,J＝6.8Hz,1H),1.74(br s,3H),1.50(d,J＝6.8Hz,3H)。
The synthesis of step 2. trifluoromethanesulfonic acid 2,4-dimethyl-5-oxo-DHF-3-base ester (C19)
To C18 (15.0g at-20 DEG C, 117mmol) and N, N-diisopropylethylamine (99%, 24.8mL, portion-wise addition trifluoromethanesulfanhydride anhydride (23.7mL in solution 140mmol) in methylene dichloride (500mL), 140mmol), adding rate is enough to make internal reaction temperature maintain less than-10 DEG C.Stirred reaction mixture at-20 DEG C, and make it be warming up to 0 DEG C gradually through 5 hours.Make reaction mixture pass silica gel plug subsequently, through dried over mgso, and concentrate in a vacuum.Residue is suspended in ether, and filters; Under reduced pressure concentrated filtrate.Use silica gel chromatography (gradient: 0% to 17% ethyl acetate in heptane) to carry out purifying, obtain the product in pale yellowish oil.Yield: 21.06g, 80.94mmol, 69%. 1H NMR(400MHz,CDCl 3)δ5.09-5.16(m,1H),1.94-1.96(m,3H),1.56(d,J＝6.6Hz,3H)。
The synthesis of step 3.2-[4-(benzyloxy)-2-aminomethyl phenyl]-4,4,5,5-tetramethyl--1,3,2-dioxas boron penta ring (C20)
By bromo-for phenmethyl 4-3-methyl phenyl ether (19g, 69mmol), [1, two (diphenylphosphino) ferrocene of 1'-] palladium chloride (II) (7.5g, 10.2mmol), potassium acetate (26.9g, 274mmol) and 4,4,4', 4', 5,5,5', 5'-prestox-2,2'-two-1,3,2-dioxa boron penta ring (20g, 79mmol) merge in Isosorbide-5-Nitrae-dioxane (500mL), and heat 2 hours under reflux.By diatomite filtration reaction mixture; Concentrated filtrate in a vacuum, and carry out purifying by silica gel chromatography (gradient: 0% to 1% ethyl acetate in sherwood oil), obtain the product in yellow gel shape.Yield: 15g, 46mmol, 67%. 1H NMR(400MHz,CDCl 3)δ7.73(d,J＝8.0Hz,1H),7.30-7.46(m,5H),6.76-6.82(m,2H),5.08(s,2H),2.53(s,3H),1.34(s,12H)。
The synthesis of step 4.4-[4-(benzyloxy)-2-aminomethyl phenyl]-3,5-dimethyl furan-2 (5H)-one (C21)
By C19 (5.0g, 19mmol), C20 (7.48g, 23.1mmol), tetrakis triphenylphosphine palladium (0) (2.22g, 1.92mmol) and sodium carbonate (4.07g, 38.4mmol) 1, merge in 4-dioxane (100mL) and water (5mL), and heat 2 hours under reflux.Filter reaction mixture, and concentrated filtrate in a vacuum.Use silica gel chromatography (elutriant: 10:1, subsequently 5:1 petrol ether/ethyl acetate) to carry out purifying, obtain the product in white solid.Yield: 5.8g, 19mmol, 100%.NMR(400MHz,CDCl 3)δ7.33-7.49(m,5H),6.98(d,J＝8.5Hz,1H),6.94(br d,J＝2.5Hz,1H),6.88(br dd,J＝8.3,2.5Hz,1H),5.20(qq,J＝6.7,1.8Hz,1H),5.09(s,2H),2.21(s,3H),1.78(d,J＝1.8Hz,3H),1.31(d,J＝6.8Hz,3H)。
The synthesis of step 5.4-[4-(benzyloxy)-2-aminomethyl phenyl]-5-hydroxyl-3,5-dimethyl furan-2 (5H)-one (C22)
By C21 (5.4g, 18mmol) and 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU, 13.3g, 87.4mmol), the solution in acetonitrile (100mL) is cooled to-60 DEG C.At-60 DEG C with oxygen to bubbling in reaction mixture 20 minutes; Stirred solution 18 hours at 50 DEG C subsequently.Concentrated reaction mixture in a vacuum, and carry out purifying by silica gel chromatography (elutriant: 5:1 petrol ether/ethyl acetate), obtain the product in colorless oil.Yield: 3.5g, 11mmol, 61%. 1h NMR (400MHz, CDCl 3), characteristic peak: δ 7.33-7.49 (m, 5H), 6.92-6.96 (m, 1H), 6.88 (dd, J=8.5,2.5Hz, 1H), 5.09 (s, 2H), 2.20 (s, 3H), 1.73 (s, 3H).
The synthesis of step 6.5-[4-(benzyloxy)-2-aminomethyl phenyl]-4,6-dimethyl pyridazine-3 (2H)-one (C23)
C22 (3.5g, 11mmol) and hydrazine hydrate (85% in water, 1.9g, the 32mmol) mixture in propyl carbinol (60mL) are heated 18 hours under reflux.After under reduced pressure removing volatile matter, stir residue 30 minutes by ethyl acetate (20mL), subsequent filtration, obtain the product in white solid.Yield: 2.0g, 6.2mmol, 56%. 1H NMR(400MHz,CDCl 3)δ10.93(br s,1H),7.33-7.51(m,5H),6.96(s,1H),6.88-6.94(m,2H),5.10(s,2H),2.04(s,3H),1.95(s,3H),1.91(s,3H)。
The synthesis of step 7.5-[4-(benzyloxy)-2-aminomethyl phenyl]-4,6-dimethyl-2-(tetrahydrochysene-2H-pyrans-2-base) pyridazine-3 (2H)-one (C24)
By C23 (1.04g, 3.25mmol), 3,4-dihydro-2H-pyrans (12.3g, 1.46mmol) and the mixture of tosic acid (59.4mg, 0.652mmol) in tetrahydrofuran (THF) (100mL) heat 24 hours under reflux.Concentrated reaction mixture in a vacuum subsequently, and distribute between ethyl acetate and water.Use dried over sodium sulfate organic layer, filter, and under reduced pressure concentrate.Silica gel chromatography (gradient: 0% to 40% ethyl acetate in heptane), obtains product jelly, from 1h NMR spectrum infers that this product is the mixture of diastereomeric atropisomer.Yield: 560mg, 1.38mmol, 42%.LCMS m/z405.3[M+H +]。 1h NMR (400MHz, CDCl 3), characteristic peak: δ 7.33-7.49 (m, 5H), 6.83-6.95 (m, 3H), 6.12-6.17 (m, 1H), 5.09 (s, 2H), 4.15-4.24 (m, 1H), 3.76-3.85 (m, 1H), 2.29-2.41 (m, 1H), 2.02 and 2.04 (2s, total 3H), 1.98 and 1.98 (2s, total 3H), 1.89 and 1.89 (2s, total 3H).
The synthesis of step 8.5-(4-hydroxy-2-methyl phenyl)-4,6-dimethyl-2-(tetrahydrochysene-2H-pyrans-2-base) pyridazine-3 (2H)-one (C25)
To C24 (1.47g, palladium (10% palladium/carbon is added in solution 3.63mmol) in methyl alcohol (30mL) and ethyl acetate (10mL), 1.16g, 1.09mmol), and under room temperature, make mixture hydrogenation (50psi) 18 hours on Pa Er oscillator (Parr shaker).By diatomite filtration reaction mixture, and use ethyl acetate rinse filter pad; The concentrated filtrate merged in a vacuum, and with heptane grinding, obtain the product in white solid, from 1h NMR spectrum judges the mixture of this product as diastereomeric atropisomer.Yield: 1.01g, 3.21mmol, 88%. 1h NMR (400MHz, CDCl 3), characteristic peak: δ 6.74-6.85 (m, 3H), 6.12-6.17 (m, 1H), 4.15-4.23 (m, 1H), 3.76-3.84 (m, 1H), 2.28-2.41 (m, 1H), 1.99 and 2.01 (2s, total 3H), 1.97 and 1.98 (2s, total 3H), 1.89 and 1.89 (2s, total 3H).
Step 9.4, the synthesis of 6-dimethyl-5-(2-methyl-4-{ [1-(tetrahydrochysene-2H-pyrans-2-base)-1H-pyrazolo [4,3-c] pyridin-4-yl] oxygen base } phenyl)-2-(tetrahydrochysene-2H-pyrans-2-base) pyridazine-3 (2H)-one (C26)
Cesium carbonate (2.06g, 6.32mmol) is added in the solution of P3 (550mg, 2.31mmol) and C25 (662mg, 2.10mmol) in Isosorbide-5-Nitrae-dioxane (40mL).After interpolation acid chloride (II) (48mg, 0.21mmol), with nitrogen purging reaction mixture 10 minutes.Introduce di-t-butyl [3,4,5,6-tetramethyl--2', 4', 6'-tri-(the third-2-base) biphenyl-2-base] phosphine (97%, 210mg, 0.42mmol), and with the of short duration purging reaction mixture of nitrogen, heat 3.5 hours at 100 DEG C subsequently.In reaction mixture and by after diatomite filtration, with the abundant flushed filter bed of ethyl acetate, and the filtrate of concentrated merging in a vacuum.Silica gel chromatography (elutriant: 10% in heptane, subsequently 30%, subsequently 50%, subsequently 90% ethyl acetate), obtains the product in brown solid, from it 1h NMR spectrum judges the mixture of this product as diastereomeric atropisomer.Yield: 690mg, 1.34mmol, 58%.LCMSm/z 516.3[M+H +]。 1h NMR (400MHz, CDCl 3), characteristic peak: δ 8.09 (s, 1H), 7.97 (d, J=6.0Hz, 1H), 7.25 (d, J=6.0Hz, 1H), 7.17-7.24 (m, 2H), [7.04 (d, J=8.2Hz) and 7.00 (d, J=8.2Hz), total 1H], 6.16 (br d, J=10.7Hz, 1H), 5.72 (dd, J=9.4,2.5Hz, 1H), 4.16-4.24 (m, 1H), 4.03-4.10 (m, 2H), 3.73-3.85 (m, 2H), 2.48-2.59 (m, 1H), 2.29-2.43 (m, 1H), 2.04 (br s, 3H), 1.95 (2s, total 3H).
Step 10. (+)-4,6-dimethyl-5-[2-methyl-4-(1H-pyrazolo [4,3-c] pyridin-4-yl oxygen base) phenyl] pyridazine-3 (2H)-one (3) and (-)-4, the synthesis of 6-dimethyl-5-[2-methyl-4-(1H-pyrazolo [4,3-c] pyridin-4-yl oxygen base) phenyl] pyridazine-3 (2H)-one (4)
C26 (807mg, 1.56mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (80mL) and methylene dichloride (80mL).Add the solution of hydrogenchloride in Isosorbide-5-Nitrae-dioxane (4M, 39.0mL, 156mmol), and at room temperature stirred reaction mixture 18 hours.After removing solvent in a vacuum, residue is distributed between saturated sodium bicarbonate aqueous solution and ethyl acetate.Be extracted with ethyl acetate water layer twice, and with the organic layer that dried over sodium sulfate merges, filter, and under reduced pressure concentrate.With triturated under ether, obtain racemize 4,6-dimethyl-5-[2-methyl-4-(1H-pyrazolo [4,3-c] pyridin-4-yl oxygen base) phenyl] pyridazine-3 (2H)-one in white solid.Yield: 396mg, 1.14mmol, 73%.LCMS m/z 348.1[M+H +]。Use supercritical fluid chromatography (post: Chiral Technologies, Chiralcel OJ-H, 5 μm; Elutriant: 1:3 methyl alcohol/carbonic acid gas) be separated resistance and turn enantiomer.Obtain the first eluted product in pale solid shape, it represents just (+) and revolves opticity, is appointed as COMPOUNDS EXAMPLE 3.Yield: 155mg, 0.446mmol, 28%.LCMS m/z 348.2[M+H +]。 1h NMR (400MHz, CD 3oD) δ 8.08 (s, 1H), 7.86 (d, J=6.2Hz, 1H), 7.26-7.30 (m, 2H), 7.22 (br dd, the half of ABX pattern, J=8.2,2.3Hz, 1H), 7.17 (half of d, AB quartet, J=8.2Hz, 1H), 2.11 (s, 3H), 2.03 (s, 3H), 1.93 (s, 3H).Retention time: 5.47 minutes (post: ChiralTechnologies, Chiralcel OJ-H, 250 × 4.6mm, 5 μm; Elutriant: 1:3 methyl alcohol/carbonic acid gas; Flow velocity: 2.5 ml/min).Second eluted product is also pale solid shape, and it represents negative (-) and revolves opticity, is appointed as COMPOUNDS EXAMPLE 4.Yield: 159mg, 0.458mmol, 29%.LCMSm/z 348.2[M+H +]。 1h NMR (400MHz, CD 3oD) δ 8.08 (s, 1H), 7.86 (d, J=6.0Hz, 1H), 7.26-7.30 (m, 2H), 7.22 (br dd, the half of ABX pattern, J=8.2,2.3Hz, 1H), 7.17 (half of d, AB quartet, J=8.2Hz, 1H), 2.11 (s, 3H), 2.03 (s, 3H), 1.93 (s, 3H).Retention time: 5.86 minutes (HPLC condition is identical with those conditions for above embodiment 3).
Embodiment 5
4-[4-(4,6-dimethyl pyrimidine-5-base)-3-methylphenoxy]-1H-pyrrolo-[3,2-c] pyridine (5)
The synthesis of step 1.5-(4-methoxyl group-2-aminomethyl phenyl)-4,6-dimethyl pyrimidines (C27)
To 2-(4-methoxyl group-2-aminomethyl phenyl)-4,4,5,5-tetramethyl--1,3,2-dioxa boron penta ring (30g, 120mmol), 5-bromo-4,6-dimethyl pyrimidine (22.5g, 120mmol) and potassiumphosphate (76.3g, 359mmol) in Isosorbide-5-Nitrae-dioxane (300mL) and water (150mL) in degased mixture add 1, two (diphenylphosphino) ferrocene of 1'-] palladium chloride (II)-dichloromethane complex (5g, 6mmol).Reacting by heating mixture 4 hours under reflux, subsequent filtration, and concentrate in a vacuum.Carry out purifying by silica gel chromatography (gradient: ethyl acetate in sherwood oil), obtain the product in brown solid.Yield: 25g, 110mmol, 92%.LCMS m/z 229.3[M+H +]。 1H NMR(300MHz,CDCl 3)δ8.95(s,1H),6.94(d,J＝8.2Hz,1H),6.87-6.89(m,1H),6.84(dd,J＝8.3,2.5Hz,1H),3.86(s,3H),2.21(s,6H),1.99(s,3H)。
The synthesis of step 2.4-(4,6-dimethyl pyrimidine-5-base)-3-methylphenol (C28)
In the solution of C27 (3.0g, 13mmol) in methylene dichloride (150mL), boron tribromide (3.8mL, 40mmol) is dropwise added at-70 DEG C.At room temperature stirred reaction mixture 16 hours, is adjusted to pH 8 with saturated sodium bicarbonate aqueous solution subsequently.By methylene dichloride (3 × 200mL) aqueous layer extracted, and with the organic layer that dried over sodium sulfate merges, filter, and concentrate in a vacuum.Silica gel chromatography (gradient: 60% to 90% ethyl acetate in sherwood oil), obtains the product in yellow solid.Yield: 1.2g, 5.6mmol, 43%.LCMS m/z 215.0[M+H +]。 1H NMR(400MHz,CDCl 3)δ8.98(s,1H),6.89(d,J＝8.0Hz,1H),6.86(d,J＝2.3Hz,1H),6.80(dd,J＝8.3,2.5Hz,1H),2.24(s,6H),1.96(s,3H)。
Step 3.4-[4-(4,6-dimethyl pyrimidine-5-base)-3-methylphenoxy]-1-{ [2-(TMS) oxyethyl group] methyl } synthesis of-1H-pyrrolo-[3,2-c] pyridine (C29)
To C28 (390mg, 1.82mmol) with 1, P1 (566mg is added in the mixture of 4-dioxane (10mL), 2.0mmol), acid chloride (II) (40mg, 0.18mmol), two (phenylbenzene phosphine) (224mg of 1,1'-naphthyl naphthalene-2,2'-bis-base, 0.360mmol) and cesium carbonate (1.76g, 5.40mmol).At 120 DEG C, stirred reaction mixture 2 hours, is cooled to room temperature subsequently, filters, and concentrates in a vacuum.Silica gel chromatography (elutriant: 70:1 methylene chloride/methanol), the product of the oily that obtains taking on a red color.Yield: 620mg, 1.35mmol, 74%. 1h NMR (400MHz, CD 3oD) δ 8.89 (s, 1H), 7.81 (d, J=6.0Hz, 1H), 7.43 (d, J=3.3Hz, 1H), 7.39 (br d, J=6Hz, 1H), 7.18-7.20 (m, 1H), 7.15 (half of d, AB quartet, J=8.3Hz, 1H), 7.11 (half of dd, ABX pattern, J=8.3,2.3Hz, 1H), 6.60 (d, J=3.3Hz, 1H), 5.60 (s, 2H), 3.52-3.58 (m, 2H), 2.28 (s, 6H), 2.02 (s, 3H), 0.85-0.91 (m, 2H) ,-0.06 (s, 9H).
Step 4.{4-[4-(4,6-dimethyl pyrimidine-5-base)-3-methylphenoxy]-1H-pyrrolo-[3,2-c] pyridine-1-base } synthesis of methyl alcohol (C30)
The solution of C29 (430mg, 0.93mmol) in trifluoroacetic acid (3mL) is stirred 1 hour at 80 DEG C.After cooling to room-temperature, filtering mixt, and concentrated filtrate in a vacuum.Silica gel chromatography (gradient: 3% to 9% methyl alcohol in methylene dichloride), obtains the product in yellow solid.Yield: 330mg, 0.92mmol, 99%.
The synthesis of step 5.4-[4-(4,6-dimethyl pyrimidine-5-base)-3-methylphenoxy]-1H-pyrrolo-[3,2-c] pyridine (5)
Ethane-1,2-diamines (300mg, 5.0mmol) is added in the solution of C30 (330mg, 0.92mmol) in methyl alcohol (8mL), and 45 DEG C of stirred reaction mixtures 1 hour.After cooling to room-temperature, enriched mixture in a vacuum, and use silica gel chromatography (elutriant: 20:1 methylene chloride/methanol) to carry out purifying, obtain the product in white solid.Yield: 256mg, 0.775mmol, 84%.LCMSm/z 331.1[M+H +]。 1h NMR (400MHz, CD 3oD) δ 8.89 (s, 1H), 7.73 (d, J=5.8Hz, 1H), 7.32 (d, J=3.0Hz, 1H), 7.23 (dd, J=5.9,0.9Hz, 1H), 7.17 (br d, J=2Hz, 1H), the 7.13 (half of d, AB quartet, J=8.3Hz, 1H), 7.09 (br dd, the half of ABX pattern, J=8.2,2.4Hz, 1H), 6.52 (dd, J=3.3,0.8Hz, 1H), 2.28 (s, 6H), 2.02 (br s, 3H).
Embodiment 6
4-[4-(4,6-dimethyl pyrimidine-5-base)-3-methylphenoxy]-1H-pyrazolo [4,3-c] pyridine (6)
The synthesis of step 1.4-[4-(4,6-dimethyl pyrimidine-5-base)-3-methylphenoxy]-1-(tetrahydrochysene-2H-pyrans-2-base)-1H-pyrazolo [4,3-c] pyridine (C31)
To C28 (225mg in salable reaction vessel, 1.05mmol) and P3 (250mg, 1.05mmol) in 1, cesium carbonate (1.03g is added in solution in 4-dioxane (10mL), 3.16mmol) and acid chloride (II) (24mg, 0.11mmol), and with nitrogen purging solution 10 minutes.Add di-t-butyl [3,4,5,6-tetramethyl--2', 4', 6'-tri-(the third-2-base) biphenyl-2-base] phosphine (97%, 104mg, 0.210mmol), and with the of short duration purging reaction mixture of nitrogen.Sealed vessel, and at 100 DEG C stirred reaction mixture 3 hours.After cooling to room-temperature, by diatomite filtration mixture, and with the washed filter bed of ethyl acetate; The concentrated filtrate merged in a vacuum, and carry out purifying by silica gel chromatography (elutriant: 20% in heptane, subsequently 50%, subsequently 100% ethyl acetate).Obtain the product in pale solid shape.Yield: 272mg, 0.655mmol, 62%.LCMS m/z 416.5[M+H +]。 1hNMR (400MHz, CDCl 3) δ 8.99 (s, 1H), 8.11 (d, J=0.6Hz, 1H), 7.99 (d, J=6.0Hz, 1H), 7.25-7.27 (m, 2H, assuming that; Part is covered by solvent peak), 7.20-7.24 (m, 1H), 7.10 (d, J=8.4Hz, 1H), 5.73 (dd, J=9.4,2.5Hz, 1H), 4.04-4.10 (m, 1H), 3.74-3.82 (m, 1H), 2.49-2.59 (m, 1H), 2.28 (s, 6H), 2.08-2.21 (m, 2H), 2.04 (s, 3H), 1.66-1.84 (s, 3H).
The synthesis of step 2.4-[4-(4,6-dimethyl pyrimidine-5-base)-3-methylphenoxy]-1H-pyrazolo [4,3-c] pyridine (6)
C31 (172mg, 0.414mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (5mL) and methylene dichloride (5mL), and is cooled to 0 DEG C.Add the solution of hydrogenchloride in Isosorbide-5-Nitrae-dioxane (4M, 1.04mL, 4.16mmol), and at room temperature stirred reaction mixture 45 hours.After removing solvent in a vacuum, residue is distributed between saturated sodium bicarbonate aqueous solution and methylene dichloride.With dichloromethane extraction water layer twice, and with the organic layer that dried over sodium sulfate merges, filter, and under reduced pressure concentrate, obtain the product in pale solid shape.Yield: 130mg, 0.392mmol, 95%.LCMS m/z 332.3[M+H +]。 1H NMR(400MHz,CDCl 3)δ9.00(s,1H),8.20(br s,1H),7.99(d,J＝6.0Hz,1H),7.28-7.30(m,1H),7.23-7.27(m,1H),7.16(dd,J＝6.0,1.0Hz,1H),7.11(d,J＝8.2Hz,1H),2.28(s,6H),2.05(s,3H)。
Embodiment 7
4,6-dimethyl-5-[4-(1H-pyrrolo-[3,2-c] pyridin-4-yl oxygen base) phenyl] pyridazine-3 (2H)-one (7)
Step 1.4-{4-[3,5-dimethyl-6-oxo-1-(tetrahydrochysene-2H-pyrans-2-base)-1,6-dihydrogen dazin-4-base] phenoxy group } synthesis of-1H-pyrrolo-[3,2-c] pyridine-1-t-butyl formate (C32)
By 5-(4-hydroxy phenyl)-4, 6-dimethyl-2-(tetrahydrochysene-2H-pyrans-2-base) pyridazine-3 (2H)-one (preparing in the mode being similar to C25 in embodiment 3 and 4) (600mg, 2.00mmol), P2 (757mg, 3.00mmol), cesium carbonate (1.95g, 5.99mmol), acid chloride (II) (44mg, 0.20mmol) and di-t-butyl [3, 4, 5, 6-tetramethyl--2', 4', 6'-tri-(the third-2-base) biphenyl-2-base] phosphine (97%, 200mg, 0.40mmol) in 1, mixture in 4-dioxane (15mL) nitrogen purging 10 minutes, and heat 18 hours at 80 DEG C subsequently.After filtration, dilute with water filtrate, and be extracted with ethyl acetate for several times.Wash the organic layer of merging with water, with saturated sodium-chloride water solution washing, through dried over mgso, filter, and concentrate in a vacuum.Carry out purifying by silica gel chromatography (gradient: 25% to 50% ethyl acetate in heptane), obtain the product in white solid.Yield: 860mg, 1.66mmol, 83%.LCMS m/z 517.1[M+H +]。 1h NMR (400MHz, CDCl 3), characteristic peak: δ 8.04 (d, J=5.8Hz, 1H), 7.80 (br d, J=5.8Hz, 1H), 7.62 (d, J=3.7Hz, 1H), 7.31-7.36 (m, 2H), 7.11-7.19 (m, 2H), 6.75 (dd, J=3.7,0.6Hz, 1H), 6.15 (dd, J=10.7,2.0Hz, 1H), 4.15-4.21 (m, 1H), 3.76-3.84 (m, 1H), 2.29-2.41 (m, 1H), 2.12 (s, 3H), 2.01 (s, 3H), 1.71 (s, 9H).
Step 2.4, the synthesis of 6-dimethyl-5-[4-(1H-pyrrolo-[3,2-c] pyridin-4-yl oxygen base) phenyl] pyridazine-3 (2H)-one (7)
Trifluoroacetic acid (5mL) is added in the solution of C32 (850mg, 1.64mmol) in methylene dichloride (15mL), and at room temperature stirred reaction mixture 18 hours.After under reduced pressure removing volatile matter, residue is dissolved in saturated sodium bicarbonate aqueous solution, and is extracted with ethyl acetate for several times.Wash the organic layer of merging with water, with saturated sodium-chloride water solution washing, through dried over mgso, filter, and concentrate in a vacuum.Gained material is suspended in ethyl acetate, stirs 10 minutes and filter, obtain the product in white solid.Yield: 280mg, 0.842mmol, 51%.LCMS m/z 333.1[M+H +]。 1H NMR(400MHz,DMSO-d 6)δ12.77(br s,1H),11.69(br s,1H),7.72(d,J＝5.8Hz,1H),7.43(dd,J＝3.2,2.3Hz,1H),7.29(s,4H),7.20(dd,J＝5.8,0.9Hz,1H),6.55(ddd,J＝3.2,2.0,0.9Hz,1H),1.97(s,3H),1.83(s,3H)。
Embodiment 8
(-)-1,5-dimethyl-6-[2-methyl-4-(1H-pyrazolo [4,3-c] pyridin-4-yl oxygen base) phenyl] pyrimidine-2,4 (1H, 3H)-diketone (8)
The synthesis of amino-1,5-dimethyl pyrimidine-2,4 (1H, the 3H)-dione hydrochloride (C33) of step 1.6-
To 2-cyanopropionate (95%, 13.2mL, 99.6mmol) and 1-MU (98%, 8.26g, the solution of sodium methylate in methyl alcohol (4.4M, 27mL, 119mmol) is added in solution 109mmol) in methyl alcohol (75mL), and reacting by heating mixture 18 hours under reflux, be cooled to room temperature subsequently.After removing solvent in a vacuum, with acetonitrile (3 × 50mL) under reduced pressure residue on evaporation repeatedly, distribute between acetonitrile (100mL) and water (100mL) subsequently.Slow interpolation 6M aqueous hydrochloric acid is until pH reaches about 2; Stir gained mixture one hour.By filtering collecting precipitation, and with t-butyl methyl ether washing, obtain the product in white solid.Yield: 15.2g, 79.3mmol, 80%.LCMS m/z 156.1[M+H +]。 1H NMR(400MHz,DMSO-d 6)δ10.38(br s,1H),6.39(s,2H),3.22(s,3H),1.67(s,3H)。
The synthesis of bromo-1,5-dimethyl pyrimidine-2,4 (1H, the 3H)-diketone (C34) of step 2.6-
To C33 (9.50g, 49.6mmol), Sodium Nitrite (5.24g, 76mmol) and cupric bromide (II) (22.4g, the 1:1 mixture (120mL) of acetonitrile and water is added in mixture 100mmol), and at room temperature stirred reaction mixture 66 hours.Adding aqueous sulfuric acid (1N, 200mL) and ethyl acetate (100mL), be precipitated, collecting this precipitation by filtering, and with water and ethyl acetate washing, obtain the product (7.70g) in faint yellow solid shape.The organic layer of filtrate is concentrated into smaller size smaller, forms extra precipitation during this period; Be separated this precipitation by filtering, and with the washing of 1:1 ethyl acetate/heptane, obtain extra product (0.4g).Total recovery: 8.1g, 37mmol, 75%.LCMS m/z 217.9[M+H +]。 1H NMR(400MHz,DMSO-d 6)δ11.58(br s,1H),3.45(s,3H),1.93(s,3H)。
The synthesis of the bromo-3-of step 3.6-(3,4-dimethoxy benezene)-1,5-dimethyl pyrimidine-2,4 (1H, 3H)-diketone (C35)
To C34 (4.00g, 18.3mmol) and 4-(chloromethyl)-1,2-dimethoxy benzene (5.16g, 1 is added in suspension 27.6mmol) in acetonitrile (80mL), 8-diazabicyclo [5.4.0] 11 carbon-7-alkene (98%, 5.57mL, 36.5mmol), and at 60 DEG C reacting by heating mixture 18 hours.After removing solvent in a vacuum, carry out Purification by silica gel chromatography (gradient: 25% to 50% ethyl acetate in heptane), obtain the product in white solid.Yield: 5.70g, 15.4mmol, 84%. 1HNMR(400MHz,CDCl 3)δ7.08-7.12(m,2H),6.80(d,J＝8.0Hz,1H),5.07(s,2H),3.88(s,3H),3.85(s,3H),3.65(s,3H),2.14(s,3H)。
Other applicable protecting group also can be used to protect " NH " group of C34.Such as, SEM, BOM or Boc can be used to replace the dimethoxy benezene in C35.
The synthesis of step 4.3-(3,4-dimethoxy benezene)-6-(4-hydroxy-2-methyl phenyl)-1,5-dimethyl pyrimidine-2,4 (1H, 3H)-diketone (C36)
To C35 (1.20g, 3.25mmol), (4-hydroxy-2-methyl phenyl) boric acid (988mg, 6.50mmol), [1, two (diphenylphosphino) ferrocene of 1'-] palladium chloride (II)-dichloromethane complex (98%, 271mg, 0.325mmol) and Isosorbide-5-Nitrae-dioxane (30mL) mixture in add wet chemical (3.0M, 3.3mL, 9.9mmol).At 100 DEG C after reacting by heating mixture 66 hours, be cooled to room temperature, with ethyl acetate and water dilution, and passed through diatomite filtration.With the organic layer of saturated sodium bicarbonate aqueous solution washing from filtrate, with saturated sodium-chloride water solution washing, through dried over mgso, filter, and concentrate in a vacuum.Use silica gel chromatography (gradient: 25% to 50% ethyl acetate in heptane) to carry out purifying, obtain the product in white foam.Yield: 650mg, 1.64mmol, 50%.LCMS m/z 397.2[M+H +]。 1h NMR (400MHz, CDCl 3) δ 7.22 (d, J=2.0Hz, 1H), 7.19 (dd, J=8.2,2.0Hz, 1H), 6.92 (d, J=8.1Hz, 1H), 6.81-6.84 (m, 2H), 6.79 (br dd, J=8.2,2.5Hz, 1H), 5.53 (br s, 1H), 5.17 (AB quartet, J aB=13.4Hz, Δ ν aB=18.8Hz, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 3.03 (s, 3H), 2.10 (br s, 3H), 1.66 (s, 3H).
Or the free OH group of (4-hydroxy-2-methyl phenyl) boric acid can be protected, subsequently by (4-hydroxy-2-methyl phenyl) boric acid and C35 coupling by the protecting group be applicable to (such as MOM or phenmethyl).In this case, the product of linked reaction through deprotection, can obtain C36.
Step 5.3-(3,4-dimethoxy benezene)-1,5-dimethyl-6-(2-methyl-4-{ [1-(tetrahydrochysene-2H-pyrans-2-base)-1H-pyrazolo [4,3-c] pyridin-4-yl] oxygen base } phenyl) pyrimidine-2, the synthesis of 4 (1H, 3H)-diketone (C37)
Be used in the method adopted when synthesizing C26 in embodiment 3 and 4 and C36 is converted into product.In the case, after by diatomite filtration and with ethyl acetate rinse filter pad, wash the organic layer of the filtrate of merging with water, with saturated sodium-chloride water solution washing, through dried over sodium sulfate, filter, and concentrate in a vacuum.Carry out purifying by silica gel chromatography (gradient: 50% to 100% ethyl acetate in heptane), obtain the product in brown solid.Yield: 490mg, 0.820mmol, 63%.LCMSm/z 598.3[M+H +]。 1h NMR (400MHz, CDCl 3), characteristic peak: δ 8.06-8.08 (m, 1H), 7.99 (d, J=6.2Hz, 1H), 7.32 (dd, J=6.2,0.9Hz, 1H), 7.24 (br d, J=2.0Hz, 1H), 7.21 (br dd, J=8.1,2.0Hz, 1H), 7.15 (d, J=8.2Hz, 1H), 6.84 (d, J=8.2Hz, 1H), 5.74 (dd, J=9.2,2.5Hz, 1H), 5.18 (AB quartet, J aB=13.4Hz, Δ ν aB=19.1Hz, 2H), 4.03-4.09 (m, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 3.74-3.82 (m, 1H), 3.11 (s, 3H), 2.21 (br s, 3H), 1.71 (s, 3H).
The synthesis of step 6. (-)-1,5-dimethyl-6-[2-methyl-4-(1H-pyrazolo [4,3-c] pyridin-4-yl oxygen base) phenyl] pyrimidine-2,4 (1H, 3H)-diketone (8)
C37 (490mg, 0.820mmol), trifluoroacetic acid (8mL) and anisole (0.446mL, 4.10mmol) is merged in penstock; Sealed tube and at 120 DEG C reacting by heating mixture 42 hours.After cooling to room-temperature, concentrated reaction mixture in a vacuum, and distribute between ethyl acetate (100mL) and saturated sodium bicarbonate aqueous solution (20mL).Order water (10mL) and wash organic layer with saturated sodium-chloride water solution (10mL), through dried over mgso, filters, and under reduced pressure concentrates.After silica gel chromatography (gradient: 65% to 100% ethyl acetate in heptane), product is carried out supercritical fluid chromatography on chiral column.Collect a kind of resistance and turn enantiomer, the product in solid state is provided; This material represents negative (-) and revolves opticity.Yield: 95mg, 0.26mmol, 32%.LCMS m/z 364.2[M+H +]。 1h NMR (400MHz, CDCl 3) δ 8.33 (br s, 1H), 8.24 (br s, 1H), 7.98 (d, J=6.1Hz, 1H), 7.27-7.32 (m, 2H, assuming that; Part is covered by solvent peak), 7.19 (dd, J=6.1,1.0Hz, 1H), 7.18 (br d, J=8Hz, 1H), 3.08 (s, 3H), 2.23 (br s, 3H), 1.70 (s, 3H).
Embodiment 9 and 10
4,6-dimethyl-5-[2-methyl-4-(1H-pyrrolo-[3,2-c] pyridin-4-yl oxygen base) phenyl] pyridazine-3 (2H)-one, ENT-1 (9) and 4,6-dimethyl-5-[2-methyl-4-(1H-pyrrolo-[3,2-c] pyridin-4-yl oxygen base) phenyl] pyridazine-3 (2H)-one, ENT-2 (10)
Step 1.4,6-dimethyl-5-{2-methyl-4-[(1-{ [2-(TMS) oxyethyl group] methyl }-1H-pyrrolo-[3,2-c] pyridin-4-yl) oxygen base] phenyl } synthesis of-2-(tetrahydrochysene-2H-pyrans-2-base) pyridazine-3 (2H)-one (C38)
Be used in embodiment 6 method described when synthesizing C31 to react to make C25 and P1.Obtain the product in solid state, based on it 1h NMR spectrum infers that described product is the mixture of diastereomeric atropisomer.Yield: 53mg, 94 μm of ol, 27%.LCMS m/z 561.4[M+H +]。 1h NMR (400MHz, CDCl 3), characteristic peak: δ 7.98 (br d, J=6Hz, 1H), 6.96-7.04 (m, 1H), 6.13-6.18 (m, 1H), 5.51 (s, 2H), 4.16-4.24 (m, 1H), 3.77-3.85 (m, 1H), 3.48-3.54 (m, 2H), 2.04 (2s, total 3H), 1.95 (2s, total 3H), 0.89-0.94 (m, 2H) ,-0.03 (s, 9H).
Step 2.4,6-dimethyl-5-[2-methyl-4-(1H-pyrrolo-[3,2-c] pyridin-4-yl oxygen base) phenyl] pyridazine-3 (2H)-one, ENT-1 (9) and 4,6-dimethyl-5-[2-methyl-4-(1H-pyrrolo-[3,2-c] pyridin-4-yl oxygen base) phenyl] pyridazine-3 (2H)-one, the synthesis of ENT-2 (10)
Trifluoroacetic acid (1mL) is added in the solution of C38 (53mg, 94 μm of ol) in methylene dichloride (3mL), and at room temperature stirred reaction mixture 18 hours.Solution is distributed between ethyl acetate and saturated sodium bicarbonate aqueous solution; Be extracted with ethyl acetate water layer three times, and the organic layer merged is merged, dry, filter, and concentrate in a vacuum.Dissolved residue in tetrahydrofuran (THF) (5mL) and water (1mL), with potassium hydroxide (300mg, 5.3mmol) process, and at room temperature stirs 18 hours.Subsequently reaction mixture is distributed between ethyl acetate and saturated aqueous ammonium chloride; Be extracted with ethyl acetate water layer three times, and the dry organic layer merged, filter, and under reduced pressure concentrate.Gained solid (40mg) is made to carry out supercritical fluid chromatography (post: Chiral Technologies, Chiralpak AS-H, 5 μm, elutriant: 7:3 carbon dioxide/methanol).The the first wash-out resistance be separated in solid state turns enantiomer, is assigned therein as compound 9.Yield: 8mg, 20 μm of ol, 20%.LCMS m/z 347.1[M+H +]。 1H NMR(400MHz,CD 3OD)δ7.78(br d,J＝5.8Hz,1H),7.36(d,J＝3.1Hz,1H),7.31(d,J＝6.0Hz,1H),7.20-7.22(m,1H),7.10-7.16(m,2H),6.39(d,J＝3.1Hz,1H),2.08(s,3H),2.02(s,3H),1.92(s,3H)。Retention time: 4.07 minutes (post: ChiralTechnologies, Chiralpak AS-H, 4.6 × 250mm, 5 μm; Elutriant: 5% methyl alcohol in carbonic acid gas continues 1.0 minutes, 5% to 50% methyl alcohol then in carbonic acid gas was through the gradient of 6.0 minutes; Flow velocity: 4.0 ml/min).The the second wash-out resistance also obtained in solid state turns enantiomer, is assigned therein as compound 10.Yield: 8mg, 20 μm of ol, 20%.LCMS m/z 347.2[M+H +]。 1hNMR (400MHz, CD 3oD) δ 7.88 (br d, J=6.4Hz, 1H), 7.47 (br d, J=6Hz, 1H), 7.45 (d, J=3.3Hz, 1H), 7.34 (br d, J=2Hz, 1H), 7.27 (br dd, the half of ABX pattern, J=8.3,2.2Hz, 1H), the 7.21 (half of d, AB quartet, J=8.4Hz, 1H), 6.16 (dd, J=3.3,0.6Hz, 1H), 2.11 (s, 3H), 2.02 (s, 3H), 1.92 (s, 3H).Retention time: 5.47 minutes (HPLC condition is identical with to those conditions described by compound 9).
Embodiment 11 and 12
4-[4-(3,5-dimethyl pyridazine-4-base)-3-methylphenoxy]-1H-pyrrolo-[3,2-c] pyridine, ENT-1 (11) and 4-[4-(3,5-dimethyl pyridazine-4-base)-3-methylphenoxy]-1H-pyrrolo-[3,2-c] pyridine, ENT-2 (12)
Step 1.4, the synthesis of the chloro-2-of 5-bis-(tetrahydrochysene-2H-pyrans-2-base) pyridazine-3 (2H)-one (C39)
By 4,5-dichloro-pyridazine-3-alcohol (42g, 250mmol), 3,4-dihydro-2H-pyrans (168g, 2.00mol) and the mixture of tosic acid (8.8g, 51mmol) in tetrahydrofuran (THF) (2L) heat 2 days under reflux.After cooling to room-temperature, concentrated reaction mixture in a vacuum, and carry out purifying by silica gel chromatography (gradient: 3% to 5% ethyl acetate in sherwood oil).Obtain the product in white solid.Yield: 42g, 170mmol, 68%. 1H NMR(400MHz,CDCl 3)δ7.84(s,1H),6.01(br d,J＝11Hz,1H),4.10-4.16(m,1H),3.70-3.79(m,1H),1.99-2.19(m,2H),1.50-1.80(m,4H)。
The synthesis of step 2.4-chloro-5-methyl-2-(tetrahydrochysene-2H-pyrans-2-base) pyridazine-3 (2H)-one (C40) and the chloro-4-methyl of 5--2-(tetrahydrochysene-2H-pyrans-2-base) pyridazine-3 (2H)-one (C41)
To C39 (40g, 0.16mol), methyl-boron-dihydroxide (9.6g, 0.16mol) and cesium carbonate (156g, 479mmol) in 1, [1 is added in mixture in 4-dioxane (500mL) and water (50mL), two (diphenylphosphino) ferrocene of 1'-] palladium chloride (II) (5g, 7mmol).At 110 DEG C, stirred reaction mixture 2 hours, is cooled to room temperature subsequently, and is concentrated in a vacuum.Carry out purifying by silica gel chromatography (gradient: 3% to 6% ethyl acetate in sherwood oil), obtain the Compound C 40 in pale-yellow solid.Yield: 9.0g, 39mmol, 24%.LCMS m/z 250.8[M+Na +]。 1H NMR(400MHz,CDCl 3)δ7.71(s,1H),6.07(dd,J＝10.7,2.1Hz,1H),4.10-4.18(m,1H),3.71-3.81(m,1H),2.30(s,3H),1.98-2.19(m,2H),1.53-1.81(m,4H)。Also obtain the C41 in pale-yellow solid.Yield: 9.3g, 41mmol, 26%.LCMS m/z 250.7[M+Na +]。 1H NMR(400MHz,CDCl 3)δ7.77(s,1H),6.02(dd,J＝10.7,2.1Hz,1H),4.10-4.17(m,1H),3.71-3.79(m,1H),2.27(s,3H),1.99-2.22(m,2H),1.51-1.79(m,4H)。
The synthesis of step 3.4-(4-methoxyl group-2-aminomethyl phenyl)-5-methyl-2-(tetrahydrochysene-2H-pyrans-2-base) pyridazine-3 (2H)-one (C42)
To (4-methoxyl group-2-aminomethyl phenyl) boric acid (200mg, 1.20mmol), C40 (250mg, 1.09mmol) and [2'-(nitrogen two base (azanidyl)-κ N) biphenyl-2-base-κ C 2] (chlorine) { dicyclohexyl [2', 4', 6'-tri-(the third-2-base) biphenyl-2-base]-λ 5-phosphine base } palladium (22mg, 28 μm of ol) adding in de-gassed solution through degassed aqueous potassium phosphate solution (0.5M, 4.37mL, 2.18mmol) in tetrahydrofuran (THF) (4mL).After at room temperature 4 hours, use diluted ethyl acetate reaction mixture; With saturated sodium-chloride water solution washing organic layer twice, with after through dried over mgso, filter, and to concentrate in a vacuum.Silica gel chromatography (elutriant: 3:7 ethyl acetate/heptane), obtains product jelly.Yield: 290mg, 0.922mmol, 85%.LCMS m/z 315.1[M+H +]。 1h NMR (400MHz, CDCl 3), be speculated as the mixture of diastereomeric atropisomer; δ 7.76 and 7.77 (2s, total 1H), [6.92 (d, J=8.4Hz) and 6.93 (d, J=8.4Hz), total 1H], 6.79-6.82 (m, 1H), 6.76 (dd, J=8.4,2.5Hz, 1H), 6.06 (dd, J=10.7,2.1Hz, 1H), 4.09-4.17 (m, 1H), 3.78 (s, 3H), 3.66-3.76 (m, 1H), 2.09-2.26 (m, 1H), 2.08 and 2.08 (2s, total 3H), 1.96-2.05 (m, 1H), 1.93 and 1.94 (2s, total 3H), 1.63-1.80 (m, 3H), 1.48-1.60 (m, 1H).
The synthesis of step 4.4-(4-methoxyl group-2-aminomethyl phenyl)-5-methyl pyridazine-3 (2H)-one (C43)
C42 (184mg, 0.585mmol) is mixed with the solution (4M, 8mL) of hydrogenchloride in Isosorbide-5-Nitrae-dioxane, and stirs 1 hour.Concentrate in a vacuum, obtain the product (140mg) in solid state, be directly used in next step.LCMS m/z 231.1[M+H +]。 1H NMR(400MHz,CD 3OD)δ7.98(br s,1H),6.98(d,J＝8.4Hz,1H),6.89(br d,J＝2.5Hz,1H),6.84(br dd,J＝8.4,2.7Hz,1H),3.82(s,3H),2.09(br s,3H),2.01(s,3H)。
The synthesis of the chloro-4-of step 5.3-(4-methoxyl group-2-aminomethyl phenyl)-5-methyl pyridazine (C44)
C43 (from abovementioned steps, 140mg) and the mixture of Phosphorus Oxychloride (1.5mL, 16mmol) are stirred 1.5 hours at 90 DEG C.After removing Phosphorus Oxychloride in a vacuum, residue is distributed between methylene dichloride (120mL) and water (20mL), and neutralizes with sodium bicarbonate.Order sodium bicarbonate aqueous solution (2 × 50mL) and water (2 × 50mL) wash organic layer, with after through dried over mgso, filter, and under reduced pressure to concentrate.Obtain product jelly.Through two step yields: 133mg, 0.535mmol, 91%.LCMSm/z 249.1[M+H +]。 1h NMR (400MHz, CDCl 3) δ 9.03 (s, 1H), 6.94 (half of d, AB quartet, J=8.2Hz, 1H), 6.84-6.91 (m, 2H), 3.87 (s, 3H), 2.11 (s, 3H), 2.03 (s, 3H).
The synthesis of step 6.4-(4-methoxyl group-2-aminomethyl phenyl)-3,5-dimethyl pyridazines (C45)
With nitrogen to the middle bubbling 10 minutes of stirring the mixture in Isosorbide-5-Nitrae-dioxane (5mL) of tetrakis triphenylphosphine palladium (0) (32mg, 28 μm of ol) and C44 (133mg, 0.535mmol).Add trimethyl aluminium (2M in toluene, 0.5mL, 1.0mmol) subsequently, and at 95 DEG C reacting by heating mixture 1.5 hours.After cooling, carrying out cancellation reaction mixture by dropwise adding methyl alcohol, using methanol dilution subsequently.By diatomite filtration mixture, and concentrated filtrate in a vacuum.Silica gel chromatography (elutriant: 5% methyl alcohol in ethyl acetate), obtains the product in oily.Yield: 94mg, 0.41mmol, 77%.LCMS m/z 229.1[M+H +]。 1H NMR(400MHz,CDCl 3)δ8.91(s,1H),6.78-6.86(m,3H),3.80(s,3H),2.32(s,3H),1.97(s,3H),1.91(s,3H)。
The synthesis of step 7.4-(3,5-dimethyl pyridazine-4-base)-3-methylphenol (C46)
Boron tribromide (the 1M solution in methylene dichloride, 13.0mL, 13.0mmol) is dropwise added in-78 DEG C of solution of C45 (740mg, 3.24mmol) in methylene dichloride (10mL).After stirring 15 minutes at-78 DEG C, through 1 hour, reaction mixture is warming up to room temperature gradually, and at room temperature stirs 2 hours.Be cooled to-78 DEG C subsequently, with anhydrous methanol (15mL) cancellation, and be warming up to room temperature.Remove solvent in a vacuum, and process residue with methyl alcohol (20mL), and heat 30 minutes under reflux.Reaction mixture, and under reduced pressure concentrate; Residue is distributed between methylene dichloride and water.With 1N aqueous sodium hydroxide solution, water layer is adjusted to pH 14, uses dichloromethane extraction more subsequently.Make water layer reach pH 6-7 by adding 1N aqueous hydrochloric acid, and stir 10 minutes; By filtering separating obtained precipitation, obtain the product in pale solid shape.Yield: 599mg, 2.80mmol, 86%.LCMS m/z215.1[M+H +]。 1H NMR(400MHz,CD 3OD)δ8.97(s,1H),6.74-6.89(m,3H),2.33(s,3H),2.07(s,3H),1.91(s,3H)。
Step 8.4-[4-(3,5-dimethyl pyridazine-4-base)-3-methylphenoxy]-1-{ [2-(TMS) oxyethyl group] methyl } synthesis of-1H-pyrrolo-[3,2-c] pyridine (C47)
Use in embodiment 2 described method when synthesizing C15 that C46 is converted into product.In the case, by silica gel chromatography (mobile phase A: methylene dichloride; Mobile phase B: 80:20:1 methylene chloride/methanol/ammonium hydroxide solution,stronger; Gradient: 0% to 25%B) carry out purifying.Obtain the product in yellow colloidal.Yield: 67mg, 0.15mmol, 65%.LCMS m/z 461.3[M+H +]。 1H NMR(400MHz,CDCl 3)δ8.98(s,1H),7.94(d,J＝5.7Hz,1H),7.16-7.26(m,4H),7.00(d,J＝8.2Hz,1H),6.68-6.72(m,1H),5.50(s,2H),3.47-3.55(m,2H),2.42(s,3H),2.07(s,3H),1.98(s,3H),0.87-0.95(m,2H),-0.04(s,9H)。
Step 9.4-[4-(3,5-dimethyl pyridazine-4-base)-3-methylphenoxy]-1H-pyrrolo-[3,2-c] pyridine, ENT-1 (11) and 4-[4-(3,5-dimethyl pyridazine-4-base)-3-methylphenoxy]-1H-pyrrolo-[3,2-c] pyridine, the synthesis of ENT-2 (12)
In the solution of C47 (44.9mg, 97.5 μm of ol) in tetrahydrofuran (THF) (1mL), add tetrabutylammonium (the 1M solution in tetrahydrofuran (THF), 1mL, 1mmol), and at 80 DEG C reacting by heating mixture 2 hours.Reaction mixture, and be extracted with ethyl acetate.With the organic layer that water and saturated sodium-chloride water solution washing merge, with after through dried over mgso, filter, and to concentrate in a vacuum.Use high performance liquid chromatography (post: Princeton Silica, 5 μm; Gradient: 5% to 100% ethanol in heptane) carry out purifying, then by supercritical fluid chromatography (post: Chiral Technologies, ChiralpakAS-H, 5 μm; Elutriant: 3:1 carbon dioxide/methanol) carry out resistance and turn stage enantiomer separation.The the first wash-out resistance obtained in solid state turns enantiomer, is appointed as compound 11.Yield: 4.1mg, 12 μm of ol, 12%.LCMS m/z 331.2[M+H +]。 1H NMR(400MHz,CDCl 3)δ8.99(s,1H),8.72(br s,1H),7.91(d,J＝5.9Hz,1H),7.23-7.27(m,2H),7.21(br dd,J＝8.2,2.3Hz,1H),7.14(dd,J＝5.8,0.9Hz,1H),7.01(d,J＝8.2Hz,1H),6.72-6.74(m,1H),2.43(s,3H),2.07(s,3H),1.99(s,3H)。Retention time: 4.43 minutes (posts: Chiral Technologies, Chiralpak AS-H, 250 × 4.6mm, 5 μm; Elutriant: 3:1 carbon dioxide/methanol; Flow velocity: 2.5 ml/min).
The the second wash-out resistance also obtained in solid state turns enantiomer, is appointed as compound 12.Yield: 4.5mg, 14 μm of ol, 14%.LCMS m/z 331.2[M+H +]。 1H NMR(400MHz,CDCl 3)δ8.99(s,1H),8.73(br s,1H),7.91(d,J＝5.9Hz,1H),7.23-7.27(m,2H),7.21(br dd,J＝8.3,2.4Hz,1H),7.14(dd,J＝5.9,1.0Hz,1H),7.01(d,J＝8.2Hz,1H),6.71-6.74(m,1H),2.43(s,3H),2.07(s,3H),1.99(s,3H)。Retention time: 6.74 minutes (HPLC condition is identical with to those conditions described by compound 11).
Embodiment 13
4-[4-(4,6-dimethyl-1-is oxidized pyrimidine-5-base)-3-methylphenoxy]-1H-pyrazolo [4,3-c] pyridine (13)
The synthesis of step 1.4-(4,6-dimethyl-1-is oxidized pyrimidine-5-base)-3-methylphenol (C48)
In 4-(4, the 6-dimethyl pyrimidine-5-base) solution of-3-methylphenol (1.0g, 4.7mmol) in methylene dichloride (25mL), 3-chloroperoxybenzoic acid (887mg, 5.14mmol) is added at 0 DEG C.Stirring reaction 2 hours at 0 DEG C, subsequently at room temperature Keep agitation 14 hours.After removing solvent in a vacuum, carry out purifying by silica gel chromatography (gradient: 0% to 100% ethyl acetate in sherwood oil), obtain product.Yield: 742mg, 3.22mmol, 69%. 1H NMR(400MHz,CDCl 3)δ9.03(s,1H),6.82-6.91(m,3H),2.30(s,3H),2.22(s,3H),1.97(s,3H)。
The synthesis of step 2.4-[4-(4,6-dimethyl-1-is oxidized pyrimidine-5-base)-3-methylphenoxy]-1-(tetrahydrochysene-2H-pyrans-2-base)-1H-pyrazolo [4,3-c] pyridine (C49)
In the solution of C48 (230mg, 1.0mmol) in acetonitrile (25mL), add P3 (238mg, 1.00mmol) and cesium carbonate (650mg, 2.0mmol), and at 110 DEG C stirred reaction mixture 60 hours.Filter reaction mixture and concentrate in a vacuum; Silica gel chromatography (gradient: 0% to 5% methyl alcohol in methylene dichloride), obtains the product in yellow solid.Yield: 290mg, 0.67mmol, 67%.
The synthesis of step 3.4-[4-(4,6-dimethyl-1-is oxidized pyrimidine-5-base)-3-methylphenoxy]-1H-pyrazolo [4,3-c] pyridine (13)
In C49 (290mg, 0.67mmol), the solution of hydrogenchloride in Isosorbide-5-Nitrae-dioxane (10mL) is added at 0 DEG C.At room temperature stirred reaction mixture 2 hours, and concentrate in a vacuum subsequently.With in ammonium hydroxide aqueous solution and residue, until pH reaches 9.After under reduced pressure removing solvent, carry out purifying by preparative silica gel thin-layer chromatography (elutriant: 10:1 methylene chloride/methanol), obtain the product in white solid.Yield: 70mg, 0.20mmol, 30%.LCMS m/z 347.9[M+H +]。 1H NMR(400MHz,CD 3OD)δ9.05(s,1H),8.15(s,1H),7.85(d,J＝6.0Hz,1H),7.33(br s,1H),7.29(d,J＝5.5Hz,1H),7.24-7.26(m,2H),2.33(s,3H),2.30(s,3H),2.09(s,3H)。
Method A
By chloro-for the 4-of N-protected 1H-pyrrolo-[3,2-c] pyridine or chloro-1H-pyrazolo [4, the 3-c] pyridine of 4-and phenols coupling
Method A describes the concrete grammar for the preparation of some compound of the present invention.
The wherein Pg in degassed Isosorbide-5-Nitrae-dioxane (1mL) is added in the phenol (0.1mmol) of 2 dram (dram) bottle Chinese style ST-2 1for compound (such as P2 or P3) (0.11mmol) of the formula ST-1 of the N-protected of protecting group.Add cesium carbonate (about 98mg, 0.3mmol), acid chloride (II) (about 2.5mg, 10 μm of ol) and di-t-butyl [3,4,5,6-tetramethyl--2', 4', 6'-tri-(the third-2-base) biphenyl-2-base] phosphine (about 10mg, 20 μm of ol), and use in order vacuum and nitrogen are filled and are made reaction mixture degassed twice.Vial shaken and at 80 DEG C heat 20 hours, be cooled to room temperature subsequently.Reaction mixture is distributed between water (1.5mL) and ethyl acetate (2.5mL), and passes through diatomite filtration; Organic layer is made to pass the 6mL solid-phase extraction column of filling with sodium sulfate.By same program aqueous layer extracted twice, and concentrate the filtrate from the merging of sodium sulfate post in a vacuum.Residue is dissolved in methylene dichloride (0.5mL), and processes with the hydrogenchloride (4M, 0.5mL, 2mmol) in Isosorbide-5-Nitrae-dioxane.At room temperature vibrate this reaction mixture 66 hours, uses ethyl acetate (2.5mL) to dilute subsequently, and with aqueous sodium hydroxide solution (6N, 0.35mL) and water (1mL) cancellation.Organic layer is made to pass the 6mL solid-phase extraction column of filling through sodium sulfate.By same program aqueous layer extracted twice, and concentrate the filtrate from the merging of sodium sulfate post in a vacuum.Use reversed-phased high performace liquid chromatographic (post: Waters XBridge C18,5 μm; Mobile phase A: 0.03% ammonium hydroxide (v/v) in water; Mobile phase B: 0.03% ammonium hydroxide (v/v) in acetonitrile; Gradient: 10% to 100%B) carry out purifying, obtain product.
Table 1. embodiment 14-29
1., by people such as A.R.Harris, the method for Tetrahedron 2011,67,9063-9066 prepares the bromo-6-Methylimidazole of required 5-also [1,2-a] pyrazine.
2., in penultimate step, use tetrakis triphenylphosphine palladium (0) and sodium carbonate to carry out coupling.
3. final deprotection tetrabutylammonium realizes.
4. prepare required 4-(imidazo [1,2-a] pyrazine-5-base)-3-methylphenol by the universal method for the synthesis of C28 in embodiment 5.
5. use trifluoroacetic acid to carry out final deprotection, use salt of wormwood process subsequently.
6. use the method described in embodiment 5 to prepare 4-(4,6-dimethyl pyrimidine-5-base) phenol.
7. carry out final deprotection with trifluoroacetic acid.
8. use in embodiment 3 and 4 described universal method when preparing C20 bromo-for 5-4,6-dimethyl pyrimidines to be converted into 4,6-dimethyl-5-(4,4,5,5-tetramethyl--1,3,2-dioxa boron penta ring-2-base) pyrimidine.According to the universal method of the synthesis C28 provided in embodiment 5, this compound is by react with the Suzuki of 2-bromo-5-methoxy benzonitrile and deprotection is converted into required 2-(4,6-dimethyl pyrimidine-5-base)-5-hydroxy-phenylformonitrile.
9. by (2,5-bis-fluoro-4-p-methoxy-phenyl) boric acid and 5-bromo-4, the Suzuki reaction mediated by tetrakis triphenylphosphine palladium (0) between 6-dimethyl pyrimidine, then boron tribromide demethylation is used to prepare required 4-(4,6-dimethyl pyrimidine-5-base)-2,5-difluorophenols.
Suzuki between bromo-4, the 6-dimethyl pyrimidines of 10.5-Yu (the fluoro-4-p-methoxy-phenyl of 2,3-bis-) boric acid react by three (dibenzalacetone) two palladium (0) and tricyclohexyl phosphine mediate; Use boron tribromide deprotection, obtain required 4-(4,6-dimethyl pyrimidine-5-base)-2,3-difluorophenols.
11. for the condition of analysis mode HPLC.Post: Waters Atlantis dC18,4.6 × 50mm, 5 μm; Mobile phase A: 0.05% trifluoroacetic acid (v/v) in water; Mobile phase B: 0.05% trifluoroacetic acid (v/v) in acetonitrile; Gradient: 5.0% to 95%B, through 4.0 minutes linear change; Flow velocity: 2 ml/min.
12. for the condition of analysis mode HPLC.Post: Waters XBridge C18,4.6 × 50mm, 5 μm; Mobile phase A: 0.03% ammonium hydroxide (v/v) in water; Mobile phase B: 0.03% ammonium hydroxide (v/v) in acetonitrile; Gradient: 5.0% to 95%B, through 4.0 minutes linear change; Flow velocity: 2 ml/min.
13. use supercritical fluid chromatography (post: Chiral Technologies Chiralcel OJ-H, 5 μm; Elutriant: 1:4 methyl alcohol/carbonic acid gas) carry out separation of racemic product.It is the first eluting isomer that resistance turns enantiomer embodiment 26, and it represents the retention time (post: Chiral Technologies Chiralcel OJ-H, 4.6 × 250mm, 5 μm that opticity and 4.28 minutes are revolved in negative (-); Elutriant: 1:4 methyl alcohol/carbonic acid gas; Flow velocity 2.5mL/min).
14. carry out separation of racemic product described in footnote 13.It is the second eluting isomer that resistance turns enantiomer embodiment 27, and it represents the retention time (analysis condition is identical with those conditions in footnote 13) that opticity and 4.97 minutes are revolved in just (+).
The condition that those conditions adopted when preparing C27 in 15. uses and embodiment 5 are similar is reacted to make Compound C 41 and C20.Gained 5-[4-(benzyloxy)-2-aminomethyl phenyl]-4-methyl-2-(tetrahydrochysene-2H-pyrans-2-base) pyridazine-3 (2H)-one, through hydrogenation, obtains 5-(4-hydroxy-2-methyl phenyl)-4-methyl-2-(tetrahydrochysene-2H-pyrans-2-base) pyridazine-3 (2H)-one.
16. use the universal method summarized when preparing C19 in embodiment 3 and 4 to prepare trifluoromethanesulfonic acid 2-methyl-5-oxo-DHF-3-base ester by the bromo-3-oxopentanoic acid methyl ester of 4-.
Table 2. embodiment 30-43
1., in penultimate step, use 4,5-two (diphenylphosphino)-9,9-dimethyl ton but not di-t-butyl [3,4,5,6-tetramethyl--2', 4', 6'-tri-(the third-2-base) biphenyl-2-base] phosphine carries out coupling.
2. required 3-methyl-4-(2-methyl isophthalic acid H-imidazo [4,5-c] pyridine-1-base) phenol prepared in the following manner: 4-methoxyl group-2-aminotoluene and the chloro-3-nitropyridine of 4-reacted, obtains N-(4-methoxyl group-2-aminomethyl phenyl)-3-nitropyridine-4-amine.After making nitro hydrogenation, gained amine ethyl orthoacetate and diacetyl oxide are carried out cyclisation, obtain 1-(4-methoxyl group-2-aminomethyl phenyl)-2-methyl isophthalic acid H-imidazo [4,5-c] pyridine, it uses boron tribromide demethylation.
3. use the universal method summarized when preparing C19 in embodiment 3 and 4 to prepare trifluoromethanesulfonic acid 2-methyl-5-oxo-DHF-3-base ester by the bromo-3-oxopentanoic acid methyl ester of 4-.
4. use in embodiment 1 described method when synthesizing C14 that bromo-for 1-2-fluoro-4-anisole is converted into intermediate 5-(the fluoro-4-p-methoxy-phenyl of 2-)-4,6-dimethyl pyrimidines.
5. bromo-for 4-3-methoxyphenol is protected with the form of its [three (the third-2-base)] silane ether; and use [1 subsequently; two (diphenylphosphino) ferrocene of 1'-] palladium chloride (II) catalyzer is translated into [3-methoxyl group-4-(4; 4; 5; 5-tetramethyl--1,3,2-dioxa boron penta ring-2-base) phenoxy group] [three (the third-2-base)] silane.Used in embodiment 5 described condition and 5-bromo-4,6-dimethyl pyrimidines when synthesizing C27 to react, obtained 5-(2-methoxyl group-4-{ [three (the third-2-base) silylation] oxygen base } phenyl)-4,6-dimethyl pyrimidines; Carrying out deprotection with fluoridizing tetraethyl ammonium, obtaining required 4-(4,6-dimethyl pyrimidine-5-base)-3-methoxyphenol.
6. carry out final deprotection with trifluoroacetic acid, then in methyl alcohol, use sodium acetate process.
7. bromo-for 2-5-hydroxy-phenylformonitrile is protected with the form of its [three (the third-2-base)] silane ether.Come and 4 for the preparation of the method for C14 according in embodiment 1,6-dimethyl-5-(4,4,5,5-tetramethyl--1,3,2-dioxa boron penta ring-2-base) pyrimidine (uses in embodiment 1 condition described when synthesizing C13 by 5-bromo-4, prepared by 6-dimethyl pyrimidine) reaction, obtain required 2-(4,6-dimethyl pyrimidine-5-base)-5-hydroxy-phenylformonitrile.
8. carry out final deprotection with hydrochloric acid.
9. by with potassium cyanide and Isosorbide-5-Nitrae, the reaction of 7,10,13,16-hexaoxacyclooctadecane-6 prepares the bromo-6-methylpyrimidine of 5--4-formonitrile HCN by the bromo-4-of 5-chloro-6-methylpyrimidine.The condition summarized in footnote 5 is used bromo-for 4-3-fluorophenol to be converted into [the fluoro-4-of 3-(4,4,5,5-tetramethyl--1,3,2-dioxa boron penta ring-2-base) phenoxy group] [three (the third-2-base)] silane.Make these two kinds of reagent carry out Suzuki reaction and desiliconization alkylation described in footnote 5, obtain 5-(the fluoro-4-hydroxy phenyl of 2-)-6-methylpyrimidine-4-formonitrile HCN.
10. for the condition of analysis mode HPLC.Post: Waters Atlantis dC18,4.6 × 50mm, 5 μm; Mobile phase A: 0.05% trifluoroacetic acid (v/v) in water; Mobile phase B: 0.05% trifluoroacetic acid (v/v) in acetonitrile; Gradient: 5.0% to 95%B, through 4.0 minutes linear change; Flow velocity: 2 ml/min.
11. use supercritical fluid chromatography (post: Chiral Technologies Chiralcel OJ-H, 5 μm; Elutriant: 1:4 methyl alcohol/carbonic acid gas) carry out separation of racemic product.It is the first eluting isomer that resistance turns enantiomer embodiment 39, and it represents the retention time (post: Chiral Technologies Chiralcel OJ-H, 4.6 × 250mm, 5 μm that opticity and 2.91 minutes are revolved in negative (-); Elutriant: 1:4 methyl alcohol/carbonic acid gas; Flow velocity 2.5mL/min).
12. carry out separation of racemic product described in footnote 11.It is the second eluting isomer that resistance turns enantiomer embodiment 40, and it represents the retention time (analysis condition is identical with those conditions in footnote 11) that opticity and 3.28 minutes are revolved in just (+).
13. in penultimate step, uses cupric iodide (I) and cesium carbonate to carry out coupling in pyridine at 100 DEG C.
14. uses are similar in embodiment 5 those conditions adopted when preparing C27 and Compound C 41 are reacted with C20.By gained 5-[4-(benzyloxy)-2-aminomethyl phenyl]-4-methyl-2-(tetrahydrochysene-2H-pyrans-2-base) pyridazine-3 (2H)-one hydrogenation, obtain 5-(4-hydroxy-2-methyl phenyl)-4-methyl-2-(tetrahydrochysene-2H-pyrans-2-base) pyridazine-3 (2H)-one.
Table 3. embodiment 44-47
1. carry out final deprotection with trifluoroacetic acid, then in methyl alcohol, use sodium acetate process.
2. use the method prepared described in P3 to prepare the chloro-3-methyl isophthalic acid of 4--(tetrahydrochysene-2H-pyrans-2-base)-1H-pyrazolo [4,3-c] pyridine.
Embodiment A A: people D1 receptors bind measures and data
By being similar to the people such as Ryman-Rasmussen, " Differential activation of adenylatecyclase and receptor internalization by novel dopamine D1receptor agonists ", those competition binding assay methods described in Molecular Pharmacology 68 (4): 1039-1048 (2005) measure the affinity of compound described herein.This radioligand binding assay uses [ 3h]-SCH23390 (radiolabeled D1 part) assesses when being bonded on D1 acceptor, the compound tested and the ability of competitive radioligand.
The LTK human cell line of expressing that overuses combines mensuration to carry out D1.For determining basic location parameter, self-saturation binding measures ligand concentration, wherein find [ 3h] K of-SCH23390 dfor 1.3nM.Self-organization concentration curve research draw, use 0.5nM [ 3h]-SCH23390 when, optimum organizes flow measurement to be every 96 orifice plate 1.75mg/mL.These parts and tissue concentration are used in time-histories research, to measure the linear of combination and equilibrium conditions.Be combined in 30 minutes and reach balance with the tissue of specified amount at 37 DEG C.By these parameters, use Polytron and in centrifuges with 40,000 × g rotates 10 minutes to make the various of specified amount and is organized in containing 2.0mM MgCl 250mM Tris (at 4 DEG C pH 7.4) in homogenize, measure K thus ivalue.By piller settling flux in measuring buffer reagent [containing 4mMMgSO 4and in the 50mM Tris of 0.5mM EDTA (at room temperature pH 7.4].By to containing testing drug (2.5 μ L) and 0.5nM [ 3h]-SCH23390 (50 μ L) 96 orifice plates in add 200 μ L organize (final volume is 250 μ L) start to hatch.Non-specific binding is measured by carrying out radioligand combination under the existence of (+)-butaclamol (D1 antagonist) (10 μMs) of saturation concentration.At 37 DEG C after 30 minute incubation period, the screen plate fast filtering working sample be coated with by Unifilter-96GF/B PEI, and rinse with 50mM Tris buffer reagent (at 4 DEG C pH 7.4).By carry out in Ecolume screen plate liquid scintillation counting(LSC) measure membrane-bound [ 3h]-SCH23390 level.IC is calculated by the linear regression carrying out concentration-response data in MicrosoftExcel 50value (concentration that the specific binding producing 50% suppresses).Calculating K is carried out according to Cheng-Prusoff equation ivalue.
K i = IC 50 1 + ( [ L ] / K d )
The wherein concentration of [L]=free radioligand, and K d=to the dissociation constant of the radioligand of D1 acceptor (to [ 3h]-SCH23390 is 1.3nM).
Embodiment B B:D1cAMP HTRF measures and data
The D1cAMP (ring-type adenosine monophosphate) HTRF (homogeneous phase time discrimination fluorescence) using and describe herein is determined as the competitive immunometric assay between the natural cAMP produced by cell and the cAMP marked with XL-665.This assay method is for measuring the ability of test compounds excitement (comprising partial agonist) D1.The kryptofix 222 marked through the anti-cAMP of Mab makes tracer agent visible.Do not obtain peak signal containing during free cAMP at sample, this is due to donor (Eu-kryptofix 222) and the proximity of acceptor (XL665) entity.Therefore, in signal and sample, the concentration of cAMP is inversely proportional to.Temporal resolution and reference measurement (em 665nm/em 620nm) make the minimum interference of substratum.CAMP HTRF is determined as commercially available, such as, from Cisbio Bioassays, IBA group.
Material and method
Material: cAMP kinetics test kit is available from Cisbio International (Cisbio 62AM4PEJ).Multidrop Combi (Thermo Scientific) for adding in mensuration.EnVision (PerkinElmer) reader is used for HTRF reading.
Cell cultures: internal build HEK293T/hD1#1 stable cell lines (Pfizer Ann Arbor).At 37 DEG C and 5%CO 2in, cell is at NuncT 500in flask in high glucose DMEM (Invitrogen11995-065), 10% in the foetal calf serum (Invitrogen 26400-044) of dialysis, 1 × MEM NEAA (Invitrogen 1140), 25mM HEPES (Invitrogen 15630), 1 × penicillin/streptomycin (Invitrogen 15070-063) and 500 μ g/mL Genenticin (Invitrogen 10131-035) to stick together cells form growth.After growth 72 or 96 hours, rinse cell with DPBS, and interpolation 0.25% trypsinase-EDTA is shifted to make cell.Add substratum subsequently, eccentric cell, and remove substratum.By cell pellet with the density settling flux of 4e7 cell/mL in the freezing substratum of cell cultures (Invitrogen 12648-056).The 1mL aliquot of obtained cell in cryogenic vial, and freezing at-80 DEG C, in measuring for D1HTRF afterwards.
D1cAMP HTRF measuring method: by frozen cell quick-thawing, settling flux in 50mL warm culture medium, and at room temperature leaves standstill 5 minutes, subsequently centrifugal (1000rpm).Remove substratum, and by cell pellet settling flux in PBS/0.5 μM of IBMX, produce 2e5 cell/mL.Use Multidrop Combi to the upper interpolation 5 μ L cells/well of the assay plate (Greiner 784085) containing 5 μ L test compounds.On each plate, also include compound control [5 μMs of Dopamine HCLs (finally) and 0.5%DMSO (finally)] for data analysis.At room temperature incubated cell and compound 30 minutes.The working solution of cAMP-D2 and anti-cAMP-kryptofix 222 is prepared according to Cisbio specification sheets.Use Multidrop in the assay plate containing test compounds and cell, add 5 μ L cAMP-D2 working solutions.Use Multidrop in the assay plate containing test compounds, cell and cAMP-D2, add 5 μ L anti-cAMP-kryptofix 222 working solution.At room temperature hatch assay plate 1 hour.EnVision plate reader use Cisbio recommend to arrange to assay plate reading.Be used in the cAMP stock solution that provides in Cisbio medicine box to generate cAMP typical curve.
Data analysis: use computer software to carry out data analysis.Percent effect is calculated from compound control group.The primary rate data from EnVision reader are used to measure ratio EC 50.In routine analyzer, use cAMP typical curve from primary rate data determination cAMP concentration.Use the cAMP data calculated to measure cAMP EC 50.
The biological data of table 4. embodiment 1-47
A. the geometrical mean that expression >=7 time measure is worth.
B. value represents unitary determination.
C. the geometrical mean that expression >=4 time measure is worth.
Except described herein except those, according to aforementioned description, multiple amendment of the present invention can be apparent to those skilled in the art.Such amendment is also intended to fall in the scope of appended claims.The each reference (comprising all patents, patent application, journal of writings, books and any other to disclose) quoted in the application is all quoted with its entirety and is added herein.

Claims (20)

1. the compound of formula I or its pharmacy acceptable salt:
Wherein:
X 1for N or CT 4;
Q 1for 5 yuan to the 6 yuan heteroaryls containing N or 5 yuan to the 6 yuan Heterocyclylalkyls containing N, it is separately optionally by a R 9replace, and further optionally by 1,2,3 or 4 R 10replace;
T 1, T 2, T 3and T 4be selected from independently of one another: H, halogen ,-CN, C 1-4alkyl, C 1-4haloalkyl, cyclopropyl, fluorine cyclopropyl, C 1-4alkoxyl group, C 1-4halogenated alkoxy and-C (=O)-O-(C 1-4alkyl);
R 1and R 2be selected from independently of one another: H, halogen ,-CN, C 1-6alkyl, C 1-6haloalkyl, C 1-6alkoxyl group, C 1-6halogenated alkoxy, C 3-6cycloalkyl ,-C (=O) OH and-C (=O)-O-(C 1-4alkyl), wherein said C 1-6alkyl and C 3-6cycloalkyl is optionally selected from following substituting group independently of one another by 1,2,3,4 or 5 separately and replaces: halo ,-OH ,-CN, C 1-4alkyl, C 1-4haloalkyl, C 1-4alkoxyl group and C 1-4halogenated alkoxy;
R 3and R 4be selected from independently of one another: H, halogen ,-OH ,-NO 2,-CN ,-SF 5, C 1-6alkyl, C 1-6haloalkyl, C 1-6halogenated alkoxy, C 2-6thiazolinyl, C 2-6alkynyl, C 3-7cycloalkyl, 4 yuan to 10 yuan Heterocyclylalkyls ,-N (R 5) (R 6) ,-N (R 7) (C (=O) R 8) ,-C (=O)-N (R 5) (R 6) ,-C (=O) R 8,-C (=O)-OR 8,-N (R 7) (S (=O) 2r 8) ,-S (=O) 2-N (R 5) (R 6) ,-SR 8and-OR 8, wherein said C 1-6alkyl, C 3-7cycloalkyl and Heterocyclylalkyl are optionally selected from following substituting group independently of one another by 1,2 or 3 separately and replace: halogen ,-CN ,-OH, C 1-4alkyl, C 1-4alkoxyl group, C 1-4haloalkyl, C 1-4halogenated alkoxy, C 3-6cycloalkyl ,-N (R 5) (R 6) ,-N (R 7) (C (=O) R 8) ,-C (=O)-OR 8,-C (=O) H ,-C (=O) R 8,-C (=O) N (R 5) (R 6) ,-N (R 7) (S (=O) 2r 8) ,-S (=O) 2-N (R 5) (R 6) ,-SR 8and-OR 8;
R 5for H, C 1-4alkyl, C 1-4haloalkyl or C 3-7cycloalkyl;
R 6for H or be selected from: C 1-4alkyl, C 1-4haloalkyl, C 3-7cycloalkyl, 4 yuan to 10 yuan Heterocyclylalkyls, C 6-10aryl, 5 yuan to 10 yuan heteroaryls, (C 3-7cycloalkyl)-C 1-4alkyl-, (4 yuan to 10 yuan Heterocyclylalkyls)-C 1-4alkyl-, (C 6-10aryl)-C 1-4alkyl-and (5 yuan to 10 yuan heteroaryls)-C 1-4alkyl-, wherein above-mentioned the respective option is optionally selected from following substituting group independently of one another by 1,2,3 or 4 and replaces :-OH ,-CN, C 1-4alkyl, C 3-7cycloalkyl, C 1-4hydroxyalkyl ,-S-C 1-4alkyl ,-C (=O) H ,-C (=O)-C 1-4alkyl ,-C (=O)-O-C 1-4alkyl ,-C (=O)-NH 2,-C (=O)-N (C 1-4alkyl) 2, C 1-4haloalkyl, C 1-4alkoxyl group and C 1-4halogenated alkoxy;
Or R 5and R 6form 4 yuan to 10 yuan Heterocyclylalkyls or 5 yuan to 10 yuan heteroaryls together with the atom N that they connect, it is optionally selected from following substituting group independently of one another by 1,2,3,4 or 5 separately and replaces: halogen ,-OH, oxo ,-C (=O) H ,-C (=O) OH ,-C (=O)-C 1-4alkyl ,-C (=O)-NH 2,-C (=O)-N (C 1-4alkyl) 2,-CN, C 1-4alkyl, C 1-4alkoxyl group, C 1-4hydroxyalkyl, C 1-4haloalkyl and C 1-4halogenated alkoxy;
R 7be selected from H, C 1-4alkyl and C 3-7cycloalkyl;
R 8be selected from C 1-6alkyl, C 3-7cycloalkyl, 4 yuan to 14 yuan Heterocyclylalkyls, C 6-10aryl, 5 yuan to 10 yuan heteroaryls, (C 3-7cycloalkyl)-C 1-4alkyl-, (4 yuan to 10 yuan Heterocyclylalkyls)-C 1-4alkyl-, (C 6-10aryl)-C 1-4alkyl-and (5 yuan to 10 yuan heteroaryls)-C 1-4alkyl-, wherein above-mentioned the respective option is optionally selected from following substituting group independently of one another by 1,2 or 3 and replaces: halogen ,-CF 3,-CN ,-OH, oxo ,-S-C 1-4alkyl, C 1-4alkyl, C 1-4haloalkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 3-7cycloalkyl, C 1-4alkoxyl group and C 1-4halogenated alkoxy;
R 9for C 1-4alkyl, C 1-4haloalkyl ,-CN ,-SF 5,-N (R 5) (R 6), C 1-6alkoxyl group, C 1-6halogenated alkoxy, C 3-7cycloalkyloxy or C 3-7cycloalkyl, wherein said C 1-4alkyl and C 3-7cycloalkyl is optionally selected from following substituting group independently of one another by 1,2,3,4 or 5 separately and replaces: halogen ,-N (R 5) (R 6), C 1-4alkyl, C 1-4haloalkyl, C 3-7cycloalkyl, C 1-4alkoxyl group and C 1-4halogenated alkoxy;
Each R 10independently selected from: halogen ,-OH ,-CN ,-SF 5,-NO 2, oxo, thiocarbonyl group, C 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 1-6alkoxyl group, C 1-6halogenated alkoxy, C 3-7cycloalkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 6-10aryl, 4 yuan to 10 yuan Heterocyclylalkyls, 5 yuan to 10 yuan heteroaryls, (C 3-7cycloalkyl)-C 1-4alkyl-, (4 yuan to 10 yuan Heterocyclylalkyls)-C 1-4alkyl-, (C 6-10aryl)-C 1-4alkyl-, (5 yuan to 10 yuan heteroaryls)-C 1-4alkyl-,-N (R 5) (R 6) ,-N (R 7) (C (=O) R 8) ,-S (=O) 2n (R 5) (R 6) ,-C (=O)-N (R 5) (R 6) ,-C (=O)-R 8,-C (=O)-OR 8,-SR 8and-OR 8, wherein said C 1-6alkyl, C 3-7cycloalkyl, C 6-10aryl, 4 yuan to 10 yuan Heterocyclylalkyls, 5 yuan to 10 yuan heteroaryls, (C 3-7cycloalkyl)-C 1-4alkyl-, (4 yuan to 10 yuan Heterocyclylalkyls)-C 1-4alkyl-, (C 6-10aryl)-C 1-4alkyl-and (5 yuan to 10 yuan heteroaryls)-C 1-4alkyl-be optionally selected from following substituting group independently of one another by 1,2,3 or 4 separately to replace: halogen, OH ,-CN ,-NO 2, C 1-4alkyl, C 1-4hydroxyalkyl, C 1-4alkoxyl group ,-N (R 5) (R 6) ,-S-(C 1-4alkyl) ,-S (=O) 2-(C 1-4alkyl), C 6-10aryloxy, [optionally by 1 or 2 C 1-4(the C that alkyl replaces 6-10aryl)-C 1-4alkyl oxy-], oxo ,-C (=O) H ,-C (=O)-C 1-4alkyl ,-C (=O) O-C 1-4alkyl ,-C (=O) NH 2,-NHC (=O) H ,-NHC (=O)-(C 1-4alkyl), C 3-7cycloalkyl, 5 yuan or 6 yuan of heteroaryls, C 1-4haloalkyl and C 1-4halogenated alkoxy;
Or R 9and contiguous R 10the Q be connected with them 1on two annular atomses form fused benzene rings together or condense 5 yuan or 6 yuan of heteroaryls, its R optionally selected independently by 1,2,3,4 or 5 separately 10areplace; And
Each R 10aindependent selected from halo ,-OH ,-N (R 5) (R 6) ,-C (=O) OH ,-C (=O)-C 1-4alkyl ,-C (=O)-NH 2,-C (=O)-N (C 1-4alkyl) 2,-CN ,-SF 5, C 1-4alkyl, C 1-4alkoxyl group, C 1-4hydroxyalkyl, C 1-4haloalkyl and C 1-4halogenated alkoxy;
Condition is the compound of described formula I is not 4-(4-imidazoles-1-base-phenoxy group)-3-methyl isophthalic acid H-pyrazolo [4,3-c] pyridine.
2. the compound of claim 1 or its pharmacy acceptable salt, wherein X 1for N.
3. the compound of claim 1 or its pharmacy acceptable salt, wherein X 1for CT 4.
4. the compound any one of claim 1-3 or its pharmacy acceptable salt, wherein T 1, T 2, T 3and T 4be selected from H, F ,-CN, methoxyl group, C independently of one another 1fluoroalkyloxy, methyl and C 1fluoroalkyl.
5. the compound any one of claim 1-4 or its pharmacy acceptable salt, wherein T 2for H and T 3for H.
6. the compound of claim 1 or its pharmacy acceptable salt, wherein said compound is the compound of formula Ia:
7. the compound of claim 1 or its pharmacy acceptable salt, wherein said compound is the compound of formula Ib:
8. the compound any one of claim 1-7 or its pharmacy acceptable salt, wherein:
R 1and R 2be selected from independently of one another: H, halogen ,-CN, C 1-4alkyl, C 1-4haloalkyl, C 1-4alkoxyl group, C 1-4halogenated alkoxy and C 3-4cycloalkyl;
R 3and R 4be selected from independently of one another: H, halogen ,-OH ,-CN, C 1-4alkyl, C 1-4haloalkyl, C 1-4halogenated alkoxy, C 3-4cycloalkyl, 4 yuan to 7 yuan Heterocyclylalkyls ,-N (R 5) (R 6) and-OR 8;
R 5and R 6be H or be selected from C independently of one another 1-4alkyl, C 1-4haloalkyl and C 3-7cycloalkyl;
Or R 5and R 6form 4 yuan to 7 yuan Heterocyclylalkyls or 5 yuan of heteroaryls together with the atom N that they connect, it is optionally selected from following substituting group independently of one another by 1,2 or 3 separately and replaces: halogen ,-CN, C 1-4alkyl, C 1-4alkoxyl group, C 3-6cycloalkyl, C 1-4haloalkyl and C 1-4halogenated alkoxy; And
R 8be selected from C 1-4alkyl, C 3-6cycloalkyl, 4 yuan to 7 yuan Heterocyclylalkyls, phenyl and 5 yuan to 6 yuan heteroaryls, it is optionally selected from following substituting group independently of one another by 1,2 or 3 separately and replaces: halogen ,-CN, C 1-4alkyl, C 1-4haloalkyl, C 3-6cycloalkyl, C 1-4alkoxyl group and C 1-4halogenated alkoxy.
9. the compound any one of claim 1-8 or its pharmacy acceptable salt, wherein R 1and R 2be H or halogen independently of one another.
10. the compound any one of claim 1-9 or its pharmacy acceptable salt, wherein R 3for H and R 4for H, halogen ,-CN, methyl or C 1haloalkyl.
Compound any one of 11. claim 1-10 or its pharmacy acceptable salt, wherein Q 1for 5 yuan to the 6 yuan heteroaryls containing N or 5 yuan to the 6 yuan Heterocyclylalkyls containing N, it is separately by a R 9replace, and further optionally by 1,2,3 or 4 R 10replace.
Compound any one of 12. claim 1-11 or its pharmacy acceptable salt, wherein:
Q 1for group (" M 1group ");
Ring Q 1afor 5 yuan to the 6 yuan heteroaryls containing N or 5 yuan to the 6 yuan Heterocyclylalkyls containing N;
represent singly-bound or double bond;
Z 1for C;
Z 2for C or N;
R 9for C 1-4alkyl, C 1-4haloalkyl, C 3-7cycloalkyl ,-CN ,-N (R 5) (R 6), C 1-6alkoxyl group, C 1-6halogenated alkoxy or C 3-7cycloalkyloxy, wherein said C 1-4alkyl and C 3-7cycloalkyl is optionally selected from following substituting group independently of one another by 1,2,3,4 or 5 separately and replaces: halogen ,-N (R 5) (R 6), C 1-4alkyl, C 1-4haloalkyl, C 3-7cycloalkyl, C 1-4alkoxyl group and C 1-4halogenated alkoxy;
Each R 10independently selected from: halogen ,-OH ,-CN ,-NO 2, oxo, thiocarbonyl group, C 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 1-6alkoxyl group, C 1-6halogenated alkoxy, C 3-7cycloalkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 6-10aryl, 4 yuan to 10 yuan Heterocyclylalkyls, 5 yuan to 10 yuan heteroaryls, (C 3-7cycloalkyl)-C 1-4alkyl-, (4 yuan to 10 yuan Heterocyclylalkyls)-C 1-4alkyl-, (C 6-10aryl)-C 1-4alkyl-, (5 yuan to 10 yuan heteroaryls)-C 1-4alkyl-, (5 yuan to 10 yuan heteroaryls)-C 2-4thiazolinyl-,-N (R 5) (R 6) ,-N (R 7) (C (=O) R 8) ,-S (=O) 2n (R 5) (R 6) ,-C (=O)-N (R 5) (R 6) ,-C (=O)-R 8,-C (=O)-OR 8and-OR 8, wherein said C 1-6alkyl, C 3-7cycloalkyl, C 6-10aryl, 4 yuan to 10 yuan Heterocyclylalkyls, 5 yuan to 10 yuan heteroaryls, (C 3-7cycloalkyl)-C 1-4alkyl-, (4 yuan to 10 yuan Heterocyclylalkyls)-C 1-4alkyl-, (C 6-10aryl)-C 1-4alkyl-, (5 yuan to 10 yuan heteroaryls)-C 1-4alkyl-and (5 yuan to 10 yuan heteroaryls)-C 2-4thiazolinyl-be optionally selected from following substituting group independently of one another by 1,2,3 or 4 separately to replace: halogen, OH ,-CN ,-NO 2, C 1-4alkyl, C 1-4hydroxyalkyl, C 1-4alkoxyl group ,-N (R 5) (R 6) ,-S-(C 1-4alkyl) ,-S (=O) 2-(C 1-4alkyl), C 6-10aryloxy, optionally by 1 or 2 C 1-4(the C that alkyl replaces 6-10aryl)-C 1-4alkyl oxy-, oxo ,-C (=O) H ,-C (=O)-C 1-4alkyl ,-C (=O) O-C 1-4alkyl ,-C (=O) NH 2,-NHC (=O) H ,-NHC (=O)-(C 1-4alkyl), C 3-7cycloalkyl, 5 yuan or 6 yuan of heteroaryls, C 1-4haloalkyl and C 1-4halogenated alkoxy;
Or R 9and contiguous R 10the ring Q be connected with them 1aon two annular atomses form fused benzene rings together or condense 5 yuan or 6 yuan of heteroaryls, its R optionally selected independently by 1,2,3,4 or 5 separately 10areplace;
Each R 10aindependently selected from: halogen ,-OH ,-C (=O) OH ,-C (=O)-C 1-4alkyl ,-C (=O)-NH 2,-C (=O)-N (C 1-4alkyl) 2,-CN, C 1-4alkyl, C 1-4alkoxyl group, C 1-4hydroxyalkyl, C 1-4haloalkyl and C 1-4halogenated alkoxy; And
M is 0,1,2,3 or 4.
Compound any one of 13. claim 1-12 or its pharmacy acceptable salt, wherein Q 1or ring Q 1afor the pyridyl, pyrimidyl, pyridazinyl or the pyrazinyl that are optionally substituted.
The compound of 14. claims 12 or its pharmacy acceptable salt, wherein M 1group is selected from: quinolyl, isoquinolyl, 1H-imidazo [4, 5-c] pyridyl, imidazo [1, 2-a] pyridyl, 1H-pyrrolo-[3, 2-c] pyridyl, imidazo [1, 2-a] pyrazinyl, imidazo [2, 1-c] [1, 2, 4] triazinyl, imidazo [1, 5-a] pyrazinyl, imidazo [1, 2-a] pyrimidyl, 1H-indazolyl, 9H-purine radicals, imidazo [1, 2-a] pyrimidyl, [1, 2, 4] triazolo [1, 5-a] pyrimidyl, isoxazole also [5, 4-c] pyridazinyl, isoxazole also [3, 4-c] pyridazinyl and [1, 2, 4] triazolo [4, 3-b] pyridazinyl, it is separately optionally by 1, 2 or 3 R 10replace, and further optionally by 1 or 2 R 10areplace, or wherein M 1group is selected from: pyrimidyl, pyrazinyl, pyridyl, pyridazinyl, 1H-pyrazolyl, 1H-pyrryl, 4H-pyrazolyl, 1H-imidazolyl, 1H-imidazolyl, 3-oxo-2H-pyridazinyl, 1H-2-oxo-pyrimidinyl, 1H-2-oxo-pyridinyl, 2,4 (1H, 3H)-dioxo-pyrimidyl and 1H-2-oxo-pyrazinyl, it is separately by R 9replace, and further optionally by 1,2 or 3 R 10replace.
The compound of 15. claims 12 or its pharmacy acceptable salt, wherein:
M 1group is
R 10afor C 1-4alkyl, C 1-4haloalkyl or C 3-7cycloalkyl; And
T is 0 or 1.
Compound any one of 16. claims 1 to 15 or its pharmacy acceptable salt, wherein R 9for C 1-4alkyl or-CN; And each R 10be C independently 1-4alkyl.
The compound of 17. claims 1 or its pharmacy acceptable salt, described compound is selected from:
4-[4-(4,6-dimethyl pyrimidine-5-base)-3-fluorophenoxy]-1H-pyrrolo-[3,2-c] pyridine;
(+)-4,6-dimethyl-5-[2-methyl-4-(1H-pyrazolo [4,3-c] pyridin-4-yl oxygen base) phenyl] pyridazine-3 (2H)-one;
(-)-4,6-dimethyl-5-[2-methyl-4-(1H-pyrazolo [4,3-c] pyridin-4-yl oxygen base) phenyl] pyridazine-3 (2H)-one;
4-[4-(4,6-dimethyl pyrimidine-5-base)-3-methylphenoxy]-1H-pyrrolo-[3,2-c] pyridine;
4-[4-(4,6-dimethyl pyrimidine-5-base)-3-methylphenoxy]-1H-pyrazolo [4,3-c] pyridine;
4,6-dimethyl-5-[4-(1H-pyrrolo-[3,2-c] pyridin-4-yl oxygen base) phenyl] pyridazine-3 (2H)-one;
(-)-1,5-dimethyl-6-[2-methyl-4-(1H-pyrazolo [4,3-c] pyridin-4-yl oxygen base) phenyl] pyrimidine-2,4 (1H, 3H)-diketone;
4,6-dimethyl-5-[2-methyl-4-(1H-pyrrolo-[3,2-c] pyridin-4-yl oxygen base) phenyl] pyridazine-3 (2H)-one, ENT-1;
4,6-dimethyl-5-[2-methyl-4-(1H-pyrrolo-[3,2-c] pyridin-4-yl oxygen base) phenyl] pyridazine-3 (2H)-one, ENT-2;
4-[4-(4,6-dimethyl-1-is oxidized pyrimidine-5-base)-3-methylphenoxy]-1H-pyrazolo [4,3-c] pyridine;
6-methyl-5-[2-methyl-4-(1H-pyrrolo-[3,2-c] pyridin-4-yl oxygen base) phenyl] imidazo [1,2-a] pyrazine;
4-[4-(4,6-dimethyl pyrimidine-5-base) phenoxy group]-1H-pyrrolo-[3,2-c] pyridine;
2-(4,6-dimethyl pyrimidine-5-base)-5-(1H-pyrrolo-[3,2-c] pyridin-4-yl oxygen base) cyanobenzene;
4-[the chloro-4-of 3-(4,6-dimethyl pyrimidine-5-base) phenoxy group]-1H-pyrrolo-[3,2-c] pyridine;
(-)-1,5-dimethyl-6-[2-methyl-4-(1H-pyrrolo-[3,2-c] pyridin-4-yl oxygen base) phenyl] pyrazine-2 (1H)-one;
4-[4-(4,6-dimethyl pyrimidine-5-base)-3-fluorophenoxy]-1H-pyrazolo [4,3-c] pyridine;
4-[4-(4,6-dimethyl pyrimidine-5-base)-3-methoxyphenoxy]-1H-pyrazolo [4,3-c] pyridine;
4-[the chloro-4-of 3-(4,6-dimethyl pyrimidine-5-base) phenoxy group]-1H-pyrazolo [4,3-c] pyridine;
(+)-1,5-dimethyl-6-[2-methyl-4-(1H-pyrazolo [4,3-c] pyridin-4-yl oxygen base) phenyl] pyrazine-2 (1H)-one;
4,6-dimethyl-5-[4-(1H-pyrazolo [4,3-c] pyridin-4-yl oxygen base) phenyl] pyridazine-3 (2H)-one; And
1,5-dimethyl-6-[4-(1H-pyrazolo [4,3-c] pyridin-4-yl oxygen base) phenyl] pyrimidine-2,4 (1H, 3H)-diketone.
18. pharmaceutical compositions, it comprises compound any one of claim 1-17 or its pharmacy acceptable salt, and pharmaceutically acceptable carrier.
The method of illness of D1 mediation (or D1 is correlated with) in 19. treatment Mammalss, described method comprises compound any one of from the claim 1-17 to described Mammals drug treatment significant quantity or its pharmacy acceptable salt.
The method of the illness of 20. treatment people, described method comprises compound any one of from the claim 1-17 to described people's drug treatment significant quantity or its pharmacy acceptable salt, and wherein said illness is selected from schizophrenia (the cognitive symptom in such as schizophrenia and negative symptom), cognitive impairment [such as relevant to schizophrenia cognitive impairment, the cognitive impairment relevant to AD, the cognitive impairment relevant to PD, the cognitive impairment relevant to pharmacotherapy (such as D2 antagonist therapy)], attention deficit hyperactivity disorder (ADHD), impulsion, compulsive gambling, excessive eating, autism spectrum disorder, mild cognitive impairment (MCI), the cognition decline that age is relevant, dull-witted (such as senile dementia, the dementia that HIV is relevant, Alzheimer, Lewy body is dull-witted, vascular dementia or volume temporal lobe type dementia), restless leg syndrome (RLS), Parkinson's disease, Huntington chorea, anxiety, dysthymia disorders (dysthymia disorders that such as age is relevant), major depressive disorder (MDD), refractory depression (TRD), bipolar disorder, chronic apathy, anhedonia, confirmed fatigue, posttraumatic stress disorder, seasonal affective disorder, social anxiety disorder, post-natal depression, serotonin syndrome, substance abuse and pharmacological dependence, drug abuse is recurred, tourette's syndrome, tardive dyskinesia, drowsiness, excess daytime somnolence, emaciation, absent minded, sexual dysfunction (after such as erective dysfunction or SSRI sexual dysfunction), migraine, systemic lupus erythematous (SLE), hyperglycemia, atherosclerosis, hyperlipemia, obesity, diabetes, septicemia, post-ischemic renal tubular necrosis, renal failure, hyponatremia, refractory edema, narcolepsy, hypertension, congestive heart failure, Post operation eye tension force is too low, somnopathy and pain.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114751855A (en) * 2022-05-23 2022-07-15 上海皓鸿生物医药科技有限公司 Preparation method of 2-bromo-4-amino-5-methylpyridine
WO2023143321A1 (en) * 2022-01-29 2023-08-03 苏州科睿思制药有限公司 Crystal form of tavapadon, and preparation method therefor and use thereof

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR112015010412A2 (en) * 2012-11-08 2017-07-11 Pfizer heteroaromatic compounds and their use as dopamine d1 ligands
ES2649144T3 (en) 2012-11-08 2018-01-10 Pfizer Inc. Heteroaromatic compounds and their use as dopamine D1 ligands
RS59018B1 (en) 2013-06-27 2019-08-30 Pfizer Heteroaromatic compounds and their use as dopamine d1 ligands
EP3134405B1 (en) 2014-04-25 2019-08-28 Pfizer Inc Heteroaromatic compounds and their use as dopamine d1 ligands
JP6239149B2 (en) 2014-04-25 2017-11-29 ファイザー・インク Heteroaromatic compounds and their use as dopamine D1 ligands
EA201691831A1 (en) 2014-04-25 2017-02-28 Пфайзер Инк. HETEROAROMATIC COMPOUNDS AND THEIR APPLICATION AS DOPAMINE D1 LIGANDS
JP6564394B2 (en) 2014-04-28 2019-08-21 ファイザー・インク Heterocyclic compounds and their use as dopamine D1 ligands
WO2015166370A1 (en) 2014-04-28 2015-11-05 Pfizer Inc. Heteroaromatic compounds and their use as dopamine d1 ligands
CN103992319B (en) * 2014-05-27 2015-09-16 天津市斯芬克司药物研发有限公司 A kind of preparation method of pyridine carboxylic acid compounds
EP3644996B1 (en) * 2017-06-28 2023-07-26 PTC Therapeutics, Inc. Methods for treating huntington's disease
JP7158425B2 (en) * 2017-06-30 2022-10-21 チェイス セラピューティクス コーポレイション NK-1 ANTAGONIST COMPOSITIONS AND USE IN TREATMENT OF DEPRESSION
JP2023531020A (en) 2020-06-22 2023-07-20 エフ・ホフマン－ラ・ロシュ・アクチェンゲゼルシャフト Sulfone derivative
CN115340500A (en) * 2021-05-14 2022-11-15 广东东阳光药业有限公司 Preparation method of sulfur-containing compound

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004113303A1 (en) * 2003-06-26 2004-12-29 Astrazeneca Ab INDAZOLE/PYRZOLO[4,3-c]PYRIDIN DERIVATIVES AS JNK INHIBITORS, COMPOSITIONS AND METHODS RELATED THERETO AS WELL AS INTERMEDIATE THEREOF
WO2006077401A1 (en) * 2005-01-19 2006-07-27 Biolipox Ab Pyrrolopyridines useful in the treatment of inflammation
CN102428084A (en) * 2009-03-19 2012-04-25 医疗技术研究局 Compounds

Family Cites Families (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR0166088B1 (en) 1990-01-23 1999-01-15 . Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof
US5376645A (en) 1990-01-23 1994-12-27 University Of Kansas Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof
US6395733B1 (en) 1995-06-07 2002-05-28 Pfizer Inc Heterocyclic ring-fused pyrimidine derivatives
GB9518953D0 (en) 1995-09-15 1995-11-15 Pfizer Ltd Pharmaceutical formulations
WO2000035298A1 (en) 1996-11-27 2000-06-22 Wm. Wrigley Jr. Company Chewing gum containing medicament active agents
GB9711643D0 (en) 1997-06-05 1997-07-30 Janssen Pharmaceutica Nv Glass thermoplastic systems
US6232320B1 (en) 1998-06-04 2001-05-15 Abbott Laboratories Cell adhesion-inhibiting antiinflammatory compounds
TW200400034A (en) 2002-05-20 2004-01-01 Bristol Myers Squibb Co Pyrazolo-pyrimidine aniline compounds useful as kinase inhibitors
SE0201980D0 (en) 2002-06-24 2002-06-24 Astrazeneca Ab Novel compounds
CA2532971A1 (en) 2003-07-14 2005-01-27 Arena Pharmaceuticals, Inc. Fused-aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
CA2572331A1 (en) 2004-07-02 2006-02-09 Exelixis, Inc. C-met modulators and method of use
ATE501148T1 (en) 2004-12-14 2011-03-15 Astrazeneca Ab PYRAZOLOPYRIMIDINE COMPOUNDS AS ANTI-TUMOR AGENTS
WO2007035428A1 (en) 2005-09-15 2007-03-29 Bristol-Myers Squibb Company Met kinase inhibitors
EP1971611B1 (en) 2005-12-21 2012-10-10 Abbott Laboratories Anti-viral compounds
JP2009529047A (en) 2006-03-07 2009-08-13 アレイ バイオファーマ、インコーポレイテッド Heterobicyclic pyrazole compounds and uses thereof
US7601716B2 (en) 2006-05-01 2009-10-13 Cephalon, Inc. Pyridopyrazines and derivatives thereof as ALK and c-Met inhibitors
WO2008037607A1 (en) 2006-09-25 2008-04-03 Basf Se Heterocyclic compounds containing carbonyl groups, and the use thereof for controlling phytopathogenic fungi
WO2008057402A2 (en) 2006-11-02 2008-05-15 Cytovia, Inc. N-aryl-isoxazolopyrimidin-4-amines and related compounds as activators of caspases and inducers of apoptosis and the use thereof
WO2008089307A2 (en) 2007-01-18 2008-07-24 Lexicon Pharmaceuticals, Inc. Delta 5 desaturase inhibitors for the treatment of pain, inflammation and cancer
WO2008089310A2 (en) 2007-01-18 2008-07-24 Lexicon Pharmaceuticals, Inc. Delta 5 desaturase inhibitors for the treatment of obesity
WO2008104077A1 (en) 2007-02-28 2008-09-04 Methylgene Inc. Small molecule inhibitors of protein arginine methyltransferases (prmts)
CA2689092C (en) 2007-06-07 2013-01-15 Amgen Inc. Raf kinase modulators and methods of use
US7829567B2 (en) 2007-10-31 2010-11-09 Kaohsiung Medical University Imino-indeno[1,2-c] quinoline derivatives, their preparation processes, and pharmaceutical compositions comprising the same
US8450343B2 (en) 2007-12-06 2013-05-28 Xianhai Huang Gamma secretase modulators
UY31984A (en) 2008-07-16 2010-02-26 Boehringer Ingelheim Int DERIVATIVES OF N-substituted 1- (3,4-difluorobenzyl) -6-oxo-1,6-dihydropyrimidin-5-carboxamides and 2- (3,4-difluorobenzyl) -3-oxo-2,3-dihydro- N-substituted 1H-pyrazol-4-carboxamides.
UY31982A (en) 2008-07-16 2010-02-26 Boehringer Ingelheim Int DERIVATIVES OF 1,2-DIHYDROPIRIDIN-3-CARBOXAMIDS N-SUBSTITUTED
MX2011002263A (en) 2008-09-10 2011-05-23 Kalypsys Inc Aminopyrimidine inhibitors of histamine receptors for the treatment of disease.
US9006252B2 (en) 2008-09-26 2015-04-14 National Health Research Institutes Fused multicyclic compounds as protein kinase inhibitors
WO2010118367A2 (en) 2009-04-10 2010-10-14 Progenics Pharmaceuticals, Inc. Antiviral pyrimidines
ES2557453T3 (en) 2009-06-09 2016-01-26 Nantbioscience, Inc. Isoquinoline, quinoline and quinazoline derivatives as inhibitors of Hedgehog signaling
MX2012000817A (en) 2009-07-21 2012-05-08 Gilead Calistoga Llc Treatment of liver disorders with pi3k inhibitors.
TW201111385A (en) 2009-08-27 2011-04-01 Biocryst Pharm Inc Heterocyclic compounds as janus kinase inhibitors
GB201008134D0 (en) 2010-05-14 2010-06-30 Medical Res Council Technology Compounds
US8299117B2 (en) 2010-06-16 2012-10-30 Metabolex Inc. GPR120 receptor agonists and uses thereof
CA2803009A1 (en) 2010-07-01 2012-01-05 Amgen Inc. Heterocyclic compounds and their use as inhibitors of pi3k activity
EP2588469A1 (en) 2010-07-02 2013-05-08 Amgen Inc. Heterocyclic compounds and their use as inhibitors of pi3k activity
ES2649144T3 (en) * 2012-11-08 2018-01-10 Pfizer Inc. Heteroaromatic compounds and their use as dopamine D1 ligands
BR112015010412A2 (en) * 2012-11-08 2017-07-11 Pfizer heteroaromatic compounds and their use as dopamine d1 ligands

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004113303A1 (en) * 2003-06-26 2004-12-29 Astrazeneca Ab INDAZOLE/PYRZOLO[4,3-c]PYRIDIN DERIVATIVES AS JNK INHIBITORS, COMPOSITIONS AND METHODS RELATED THERETO AS WELL AS INTERMEDIATE THEREOF
WO2006077401A1 (en) * 2005-01-19 2006-07-27 Biolipox Ab Pyrrolopyridines useful in the treatment of inflammation
CN102428084A (en) * 2009-03-19 2012-04-25 医疗技术研究局 Compounds

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023143321A1 (en) * 2022-01-29 2023-08-03 苏州科睿思制药有限公司 Crystal form of tavapadon, and preparation method therefor and use thereof
CN114751855A (en) * 2022-05-23 2022-07-15 上海皓鸿生物医药科技有限公司 Preparation method of 2-bromo-4-amino-5-methylpyridine
CN114751855B (en) * 2022-05-23 2024-05-07 上海皓鸿生物医药科技有限公司 Preparation method of 2-bromo-4-amino-5-methylpyridine

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